Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same

ABSTRACT

Biodegradable, flowable or flexible polymer compositions are described comprising a polymer having the recurring monomeric units shown in formula I:                    
     wherein: 
     each of R and R′ is independently straight or branched alkylene, either unsubstituted or substituted with one or more non-interfering substituents; 
     L is a divalent cycloaliphatic group; 
     R″ is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and 
     n is 5 to 1,000, 
     wherein said biodegradable polymer is biocompatible before and upon biodegradation. In one embodiment, one or more of R, R′ or R″ is a biologically active substance. Amorphous compositions containing a biologically active substance, in addition to the polymer, and methods for controllably releasing biologically active substances using the compositions, are also described.

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 08/841,345, filed Apr. 30, 1997, now abandoned, thecontents of which are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to biodegradable poly(phosphoester)compositions that degrade in vivo into non-toxic residues, in particularthose containing a cycloaliphatic structure in the polymer backbone. Thecompositions of the invention are particularly useful as flexible orflowable materials for localized, controlled drug delivery systems.

2. Description of the Prior Art

Biocompatible polymeric materials have been used extensively intherapeutic drug delivery and medical implant applications. If a medicalimplant is intended for use as a drug delivery or othercontrolled-release system, using a biodegradable polymeric carrier isone effective means to deliver the therapeutic agent locally and in acontrolled fashion, see Langer et al., “Chemical and Physical Structuresof Polymers as Carriers for Controlled Release of Bioactive Agents”, J.Macro. Science, Rev. Macro. Chem. Phys., C23(1), 61-126 (1983). As aresult, less total drug is required, and toxic side effects can beminimized. Polymers have been used for some time as carriers oftherapeutic agents to effect a localized and sustained release. SeeLeong et al., “Polymeric Controlled Drug Delivery”, Advanced DrugDelivery Rev., 1:199-233 (1987); Langer, “New Methods of Drug Delivery”,Science, 249:1527-33 (1990) and Chien et al., Novel Drug DeliverySystems (1982). Such delivery systems offer the potential of enhancedtherapeutic efficacy and reduced overall toxicity.

When a non-biodegradable polymer matrix is used, the steps leading torelease of the therapeutic agent are water diffusion into the matrix,dissolution of the therapeutic agent, and diffusion of the therapeuticagent out through the channels of the matrix. As a consequence, the meanresidence time of the therapeutic agent existing in the soluble state isnormally longer for a non-biodegradable matrix than for a biodegradablematrix, for which passage through the channels of the matrix, while itmay occur, is no longer required.

Since many pharmaceuticals have short half-lives, therapeutic agents candecompose or become inactivated within the non-biodegradable matrixbefore they are released. This issue is particularly significant formany bio-macromolecules, e.g., proteins and smaller polypeptides, sincethese molecules are generally hydrolytically unstable and have markedlylow permeabilities through most polymer matrices. In nonbiodegradablematrices, many bio-macromolecules even begin to aggregate andprecipitate out of solution, blocking the very channels necessary fordiffusion out of the carrier matrix.

These problems are alleviated somewhat by using a biodegradable rigidmatrix that, in addition to some diffusional release, primarily allowsthe controlled release of the therapeutic agent by degradation of thesolid polymer matrix. Examples of classes of synthetic polymers thathave been studied as possible solid biodegradable materials includepolyesters (Pitt et al., “Biodegradable Drug Delivery Systems Based onAliphatic Polyesters: Applications to Contraceptives and NarcoticAntagonists”, Controlled Release of Bioactive Materials, 19-44 (RichardBaker ed., 1980); poly(amino acids) and pseudo-poly(amino acids)(Pulapura et al. “Trends in the Development of Bioresorbable Polymersfor Medical Applications”, J. Biomaterials Appl., 6:1, 216-50 (1992);polyurethanes (Bruin et al., “Biodegradable Lysine Diisocyanate-basedPoly(Glycolide-co-ε Caprolactone)-Urethane Network in Artificial Skin”,Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al.,“Release of Norethindrone from Poly(Ortho Esters)”, Polymer EngineeringSci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al.,“Polyanhydrides for Controlled Release of Bioactive Agents”,Biomaterials 7:5, 364-71 (1986).

Polymers having phosphate linkages, called poly(phosphates),poly(phosphonates) and poly(phosphites), are known. See Penczek et al.,Handbook of Polymer Synthesis, Chapter 17: “Phosphorus-ContainingPolymers”, (Hans R. Kricheldorf ed., 1992). The respective structures ofthese three classes of compounds, each having a different side chainconnected to the phosphorus atom, are as follows:

The versatility of these polymers comes from the versatility of thephosphorus atom, which is known for a multiplicity of reactions. Itsbonding can involve the 3porbitals or various 3s-3p hybrids; spd hybridsare also possible because of the accessible dorbitals. Thus, thephysico-chemical properties of the poly(phosphoesters) can be readilychanged by varying either the R or R′ group. The biodegradability of thepolymer is due primarily to the physiologically labile phosphoester bondin the backbone of the polymer. By manipulating the backbone or the sidechain, a wide range of biodegradation rates are attainable.

An additional feature of poly(phosphoesters) is the availability offunctional side groups. Because phosphorus can be pentavalent, drugmolecules or other biologically active substances can be chemicallylinked to the polymer. For example, drugs with —O-carboxy groups may becoupled to the phosphorus via a phosphoester bond, which ishydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. TheP—O—C group in the backbone also lowers the glass transition temperatureof the polymer and, importantly, confers solubility in common organicsolvents, which is desirable for easy characterization and processing.

However, drug-delivery systems using most of the known biodegradablepolymers, including those of phosphoesters, have been rigid materials.In such instances, the drug is incorporated into the polymer, and themixture is shaped into a certain form, such as a cylinder, disc, orfiber for implantation.

However, proteins and other large biomolecules are still difficult todeliver from rigid biodegradables because these larger molecules areparticularly unstable and are typically degraded along with the solidpolymeric matrix carrier. More specifically, when a polymer begins todegrade following administration, a highly concentrated microenvironmentis created from the breakdown by-products of the polymer as the polymerbecomes ionized, protonated or hydrolyzed. Proteins are easily denaturedor degraded under these conditions and then are useless for therapeuticpurposes.

Further, in the process of preparing rigid drug delivery systems,biologically active substances such as proteins are commonly exposed toextreme stresses. Necessary manufacturing steps may include excessiveexposure to heat, pH extremes, large amounts of organic solvents,cross-linking agents, freezing and drying. Following manufacture orpreparation, the drug delivery systems must be stored for some extendedperiod of time prior to administration, and little information isavailable on the subject of long term stability of proteins within solidbiodegradable delivery systems.

Rigid polymers can be inserted into the body with a syringe or catheterin the form of small particles, such as microspheres or microcapsules.However, because they are still solid particles, they do not form thecontinuous and nearly homogeneous, monolithic matrix that is sometimesneeded for preferred release profiles.

In addition, microspheres or microcapsules prepared from these polymersand containing biologically active substances to be released into thebody are sometimes difficult to produce on a large scale. Most of themicroencapsulation processes involve high temperature and contact withorganic solvents, steps that tend to damage the bioactivity of proteins.Moreover, their storage often presents problems and, upon injection,their granular nature can cause blockages in injection devices and/orirritation of the soft tissues into which the small particles areinjected.

Dunn et al., U.S. Pat. Nos. 5,278,201; 5,278,202; and 5,340,849,disclose a thermoplastic drug delivery system in which a solid,linear-chain, biodegradable polymer or copolymer is dissolved in asolvent to form a liquid solution. Once the polymer solution is placedinto the body where there is sufficient water, the solvent dissipates ordiffuses away from the polymer leaving it to coagulate or solidify intoa solid substance. However, the system requires the presence of asolvent, and it is difficult to find an organic solvent that issufficiently non-toxic for acceptable biocompatibility.

Thus, there exists a need for a composition and method for providing aflexible or flowable biodegradable composition that can be used in vivoto release a variety of different biologically active substances,including hydrophobic drugs and even large and bulky biomacromolecules,such as therapeutically useful proteins, preferably without requiringthe presence of significant amounts of organic solvent. There is also acontinuing need for biodegradable polymer compositions that may providecontrolled release in such a way that trauma to the surrounding softtissues can be minimized.

Coover et al., U.S. Pat. No. 3,271,329, discloses organophosphoruspolymers prepared from dialkyl or diaryl hydrogen phosphites and certaindiol compounds, such as 1,4-cyclohexanedimethanol. See column 1, lines24-31. Vandenberg et al., U.S. Pat. No. 3,655,585, discloses phosphorouspolymers having at least one recurring unit having the formula:

where R can be alkyl and Z can be alkylene such as cyclohexylene. Seecolumn 1, lines 28-55. Herwig et al., U.S. Pat. No. 3,875,263, disclosesdiphosphinic acid esters having a cyclic alkylene portion, e.g.,1,4-methylene-cyclohexane. See column 1, lines 18-37 and column 2, line13.

However, all of these patents suggest that such compounds and polymericcompositions made from such compounds should be extruded or molded toform articles or spun into fibers (Coover et al.); used as additives forlubricating oils, gasoline, and synthetic resins or other polymers(Vandenberg et al. and Herwig et al.); or used as coating compounds(Herwig et al.). These compounds are known by those of skill in the artprimarily as conferring high flame resistance and fire-proofingcapabilities (Coover et al. and Herwig et al.) or increased stability tooxidation and heat and improved impact strength (Vandenberg et al.).

SUMMARY OF THE INVENTION

It has now been discovered that polymer compositions made withpoly(cycloaliphatic phosphoester) compounds provide convenientlyflexible or flowable carriers for even large and/or bulkybio-macromolecules, including hydrophobic drugs and even large and bulkybio-macromolecules, such as therapeutically useful proteins. Thebiodegradable polymer composition of the invention comprises a polymerhaving the recurring monomeric units shown in formula I:

wherein:

each of R and R′ is independently straight or branched aliphatic, eitherunsubstituted or substituted with one or more non-interferingsubstituents;

L is a divalent cycloaliphatic group;

R″ is selected from the group consisting of H, alkyl, alkoxy, aryl,aryloxy, heterocyclic or heterocycloxy; and

n is 5 to 1,000

wherein the biodegradable polymer composition is biocompatible bothbefore and upon biodegradation. In a particularly preferred embodiment,one or more of R, R′ and R″ is a biologically active substance in a formcapable of being released in a physiological environment.

The invention also comprises a flexible article useful for implantation,injection, or otherwise placed totally or partially within the body, thearticle comprising a biodegradable, flowable or flexible polymercomposition comprising a polymer having the recurring monomeric unitsshown in formula I where R, R′, R″, L and n are as defined above.

In yet another embodiment of the invention, a method is provided for thecontrolled release of a biologically active substance comprising thesteps of:

(a) combining the biologically active substance with a biodegradablepolymer having the recurring monomeric units shown in formula I:

 where R, R′, L, R″ and n are as defined above, to form an implantableor injectable polymer composition; and

(b) placing the polymer composition formed in step (a) either partiallyor totally within the body at a preselected site in vivo, such that thepolymer composition is in at least partial contact with a biologicalfluid.

Because the compositions of the invention are preferably viscous,flowable “gel-like” materials or flexible materials, they can be used todeliver a wide variety of drugs, for example, from hydrophobic drugssuch as paclitaxel to large water-soluble macromolecules such asproteins. Even when not flowable, the compositions of the invention arestill flexible and allow large proteins to, at least partially, diffusethrough the matrix prior to the protein being degraded. The inventionthus provides a delivery system that is both convenient for use andcapable of delivering large bio-macromolecules in an effective manner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of P(trans-CHDM-HOP) as determined by ³¹P-NMRand ¹H-NMR.

FIG. 2 shows the chromatogram and molecular weight distribution forP(cis-/trans-CHDM-HOP).

FIG. 3A graphically represents the active energy as a function offrequency of P(trans- CHDM-HOP), and FIG. 3B shows temperaturedependence of the corresponding viscosity.

FIG. 4A shows HEK293 cells grown on a P(CHDM-HOP) surface after 72 hoursof incubation, and FIG. 4B shows HEK293 cells grown on a TCPS surfaceafter 72 hours of incubation.

FIG. 5 graphically represents the effect of the side chain structure onthe in vitro degradation rate of three poly(phosphoesters) of theinvention in phosphate buffer solution.

FIG. 6 shows the release curves of the bio-macromolecule FITC-BSA fromthe polymer P(CHDM-HOP) at 33% loading.

FIG. 7 graphically represents the in vitro release kinetics of FITC-BSAas a function of a loading levels of 30%, 10% and 1%.

FIG. 8 graphically represents the in vitro effect of side chainstructure on the protein release kinetics of FITC-BSA with a 10% loadinglevel.

FIG. 9 shows the release of low molecular weight drugs (doxorubicin,cisplatin, and 5-fluorouracil) from P(CHDM-HOP).

FIG. 10 graphically represents the simultaneous release of cisplatin anddoxorubicin from a P(CHDM-HOP) matrix.

FIG. 11 graphically represents the cumulative percentage of releasedIL-2 from the P(CHDM-HOP) matrix in phosphate butter as a function oftime.

FIG. 12 shows the calibration curves for the cumulative percentagerelease of IL-2 from a P(CHDM-HOP) matrix in phosphate buffer.

FIG. 13 compares the pharmacokinetics of IL-2 administered as asubcutaneous bolus or dispersed in a P(CHDM-HOP) matrix.

FIG. 14 shows the results of a histological examination of asubcutaneous injection site in a Balb/c mouse.

FIG. 15 shows the distribution of tumor sizes in mice four weeks aftertumor implantation in an in vivo melanoma tumor model.

FIG. 16 shows the distribution of tumor sizes in mice six weeks aftertumor implantation in an in vivo melanoma tumor model.

FIG. 17 shows the percentage of survival as a function of time for fourdifferent treatment groups in an in vivo melanoma tumor model.

FIG. 18 shows the release curves of two polymer compositions of theinvention, one comprising the chemotherapeutic agent paclitaxel in thepolymer P(CHDM-EOP) and the other comprising paclitaxel in the polymerP(CHDM-HOP).

FIG. 19 shows the in vitro release curves of lidocaine from threedifferent samples of P(CHDM-HOP)/lidocaine mixture.

FIG. 20A shows the cumulative amount of lidocaine released in vitro as afunction of incubation time, and FIG. 20B shows lidocaine release as afunction of the square root of time.

FIG. 21 plots the percentage of maximum nociceptive effect versus timeafter in vivo injection of 25 mg of lidocaine in P(CHDM-HOP) or insaline solution.

FIG. 22 plots the percentage of maximum motor function effect versustime after injection of 25 mg of lidocaine in P(CHDM-HOP) or in salinesolution.

FIG. 23 shows the lidocaine concentration in plasma following injectionof 25 mg of lidocaine in saline solution, of 25 mg of lidocaine inP(CHDM-HOP), and of 50 mg of lidocaine in P(CHDM-HOP).

DETAILED DESCRIPTION OF THE INVENTION

Polymeric Compositions of the Invention

As used herein, the term “aliphatic” refers to a linear, branched orcyclic alkane, alkene, or alkyne. Preferred linear or branched aliphaticgroups in the poly(cycloaliphatic phosphoester) composition of theinvention have from about 1 to 20 carbon atoms. Preferred cycloaliphaticgroups may have one or more sites of unsaturation, i.e., double ortriple bonds, but are not aromatic in nature.

As used herein, the term “aryl” refers to an unsaturated cyclic carboncompound with 4n+2 π electrons. As used herein, the term “heterocyclic”refers to a saturated or unsaturated ring compound having one or moreatoms other than carbon in the ring, for example, nitrogen, oxygen orsulfur.

As used herein, the term “non-interfering substituent” means asubstituent that does react with the monomers; does not catalyze,terminate or otherwise interfere with the polymerization reaction; anddoes not react with the resulting polymer chain through intra- orinter-molecular reactions.

The biodegradable and injectable polymer composition of the inventioncomprises a polymer having the recurring monomeric units shown informula I:

wherein each of R and R′ is independently straight or branchedaliphatic, either unsubstituted or substituted with one or morenon-interfering substituents. Each of R and R′ can be any aliphaticmoiety so long as the moiety does not interfere undesirably with thepolymerization or biodegradation reactions of the polymer.

Preferably, R and R′ have from about 1-20 carbon atoms. For example,each of R and R′ can be an alkylene group, such as methylene, ethylene,1,2-dimethylethylene, n-propylene, isopropylene, 2-methylpropylene,2,2-dimethylpropylene or tert-butylene, n-pentylene, tert-pentylene,n-hexylene, n-heptylene and the like; alkenylene, such as ethenylene,propenylene, dodecenylene, and the like; alkynylene, such aspropynylene, hexynylene, octadecenynylene, and the like; an aliphaticgroup substituted with a non-interfering substituent, for example,hydroxy-, halogen- or nitrogen-substituted aliphatic group. Preferably,however, each of R and R′ is a branched or straight chain alkylene groupand, even more preferably, an alkylene group having from 1 to 7 carbonatoms. Most preferably, R is a methylene or ethylene group.

In one embodiment of the invention, either R, R′, or both R and R′, canbe a biologically active substance in a form capable of being releasedin a physiological environment. When the biologically active substanceis part of the poly(phosphoester) backbone in this way, it is releasedas the polymeric matrix formed by the composition of the inventiondegrades.

Generally speaking, the biologically active substance of the inventioncan vary widely with the purpose for the composition. The term“biologically active substance” includes without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of a disease orillness; substances which affect the structure or function of the body;or pro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment. Theactive substance(s) may be described as a single entity or a combinationof entities.

Non-limiting examples of broad categories of biologically activesubstances include the following expanded therapeutic categories:β-adrenergic blocking agents, anabolic agents, androgenic steroids,antacids, anti-asthmatic agents, anti-allergenic materials,anti-cholesterolemic and anti-lipid agents, anti-cholinergics andsympathomimetics, anti-coagulants, anti-convulsants, anti-diarrheals,anti-emetics, anti-hypertensive agents, anti-infective agents,anti-inflammatory agents such as steroids, non-steroidalanti-inflammatory agents, anti-malarials, anti-manic agents,anti-nauseants, anti-neoplastic agents, anti-obesity agents,anti-parkinsonian agents, anti-pyretic and analgesic agents,anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents,anti-anginal agents, antihistamines, anti-tussives, appetitesuppressants, benzophenanthridine alkaloids, biologicals, cardioactiveagents, cerebral dilators, coronary dilators, decongestants, diuretics,diagnostic agents, erythropoietic agents, estrogens, expectorants,gastrointestinal sedatives, humoral agents, hyperglycemic agents,hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineralsupplements, miotics, imucolytic agents, neuromuscular drugs,nutritional substances, peripheral vasodilators, progestational agents,prostaglandins, psychic energizers, psychotropics, sedatives,stimulants, thyroid and anti-thyroid agents, tranquilizers, uterinerelaxants, vitamins, antigenic materials, and pro-drugs.

Specific examples of useful biologically active substances from theabove categories include: (a) anti-neoplastics such as androgeninhibitors, antimetabolites, cytotoxic agents, and immunomodulators; (b)anti-tussives such as dextromethorphan, dextromethorphan hydrobromide,noscapine, carbetapentane citrate, and chlorphedianol hydrochloride; (c)antihistamines such as chlorpheniramine maleate, phenindamine tartrate,pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate;(d) decongestants such as phenylephrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, andephedrine; (e) various alkaloids such as codeine phosphate, codeinesulfate, and morphine; (f) mineral supplements such as potassiumchloride, zinc chloride, calcium carbonate, magnesium oxide, and otheralkali metal and alkaline earth metal salts; (g) ion exchange resinssuch as cholestryramine; (h) anti-arrhythmics such asN-acetylprocainamide; (i) antipyretics and analgesics such asacetaminophen, aspirin and ibuprofen; (j) appetite suppressants such asphenyl-propanolamine hydrochloride or caffeine; (k) expectorants such asguaifenesin; (l) antacids such as aluminum hydroxide and magnesiumhydroxide; (m) biologicals such as peptides, polypeptides, proteins andamino acids, hormones, interferons or cytokines and other bioactivepeptidic compounds, such as hGH, tPA, calcitonin, ANF, EPO and insulin;(n) anti-infective agents such as anti-fungals, anti-virals, antisepticsand antibiotics; and (m) desensitizing agents and antigenic materials,such as those useful for vaccine applications.

More specifically, non-limiting examples of useful biologically activesubstances include the following therapeutic categories: analgesics,such as nonsteroidal anti-inflammatory drugs, opiate agonists andsalicylates; antihistamines, such as H₁-blockers and H₂-blockers;anti-infective agents, such as antihelmintics, antianaerobics,antibiotics, aminoglycoside antibiotics, antifungal antibiotics,cephalosporin antibiotics, macrolide antibiotics, miscellaneous β-lactamantibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamideantibiotics, tetracycline antibiotics, antimycobacterials,antituberculosis antimycobacterials, antiprotozoals, antimalarialantiprotozoals, antiviral agents, anti-retroviral agents, scabicides,and urinary anti-infectives; antineoplastic agents, such as alkylatingagents, nitrogen mustard alkylating agents, nitrosourea alkylatingagents, antimetabolites, purine analog antimetabolites, pyrimidineanalog antimetabolites, hormonal antineoplastics, naturalantineoplastics, antibiotic natural antineoplastics, and vinca alkaloidnatural antineoplastics; autonomic agents, such as anticholinergics,antimuscarinic anticholinergics, ergot alkaloids, parasympathomimetics,cholinergic agonist parasympathomimetics, cholinesterase inhibitorparasympathomimetics, sympatholytics, α-blocker sympatholytics,β-blocker sympatholytics, sympathomimetics, and adrenergic agonistsympathomimetics; cardiovascular agents, such as antianginals, β-blockerantianginals, calcium-channel blocker antianginals, nitrateantianginals, antiarrhythmics, cardiac glycoside antiarrhythmics, classI antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics,class IV antiarrhythmics, antihypertensive agents, α-blockerantihypertensives, angiotensin-converting enzyme inhibitor (ACEinhibitor) antihypertensives, β-blocker antihypertensives,calcium-channel blocker antihypertensives, central-acting adrenergicantihypertensives, diuretic antihypertensive agents, peripheralvasodilator antihypertensives, antilipemics, bile acid sequestrantantilipemics, HMG-CoA reductase inhibitor antilipemics, inotropes,cardiac glycoside inotropes, and thrombolytic agents; dermatologicalagents, such as antihistamines, anti-inflammatory agents, corticosteroidanti-inflammatory agents, antipruritics/local anesthetics, topicalanti-infectives, antifungal topical anti-infectives, antiviral topicalanti-infectives, and topical antineoplastics; electrolytic and renalagents, such as acidifying agents, alkalinizing agents, diuretics,carbonic anhydrase inhibitor diuretics, loop diuretics, osmoticdiuretics, potassium-sparing diuretics, thiazide diuretics, electrolytereplacements, and uricosuric agents; enzymes, such as pancreatic enzymesand thrombolytic enzymes; gastrointestinal agents, such asantidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents,salicylate gastrointestinal anti-inflammatory agents, antacid anti-ulceragents, gastric acid-pump inhibitor anti-ulcer agents, gastric mucosalanti-ulcer agents, H₂-blocker anti-ulcer agents, cholelitholytic agents,digestants, emetics, laxatives and stool softeners, and prokineticagents; general anesthetics, such as inhalation anesthetics, halogenatedinhalation anesthetics, intravenous anesthetics, barbiturate intravenousanesthetics, benzodiazepine intravenous anesthetics, and opiate agonistintravenous anesthetics; hematological agents, such as antianemiaagents, hematopoietic antianemia agents, coagulation agents,anticoagulants, hemostatic coagulation agents, platelet inhibitorcoagulation agents, thrombolytic enzyme coagulation agents, and plasmavolume expanders; hormones and hormone modifiers, such asabortifacients, adrenal agents, corticosteroid adrenal agents,androgens, antiandrogens, antidiabetic agents, sulfonylurea antidiabeticagents, antihypoglycemic agents, oral contraceptives, progestincontraceptives, estrogens, fertility agents, oxytocics, parathyroidagents, pituitary hormones, progestins, antithyroid agents, thyroidhormones, and tocolytics; immunobiologic agents, such asimmunoglobulins, immunosuppressives, toxoids, and vaccines; localanesthetics, such as amide local anesthetics and ester localanesthetics; musculoskeletal agents, such as anti-gout anti-inflammatoryagents, corticosteroid anti-inflammatory agents, gold compoundanti-inflammatory agents, immunosuppressive anti-inflammatory agents,nonsteroidal anti-inflammatory drugs (NSAIDs), salicylateanti-inflammatory agents, skeletal muscle relaxants, neuromuscularblocker skeletal muscle relaxants, and reverse neuromuscular blockerskeletal muscle relaxants; neurological agents, such as anticonvulsants,barbiturate anticonvulsants, benzodiazepine anticonvulsants,anti-migraine agents, anti-parkinsonian agents, anti-vertigo agents,opiate agonists, and opiate antagonists; ophthalmic agents, such asanti-glaucoma agents, β-blocker anti-glaucoma agents, mioticanti-glaucoma agents, mydriatics, adrenergic agonist mydriatics,antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmicanti-infectives, ophthalmic aminoglycoside anti-infectives, ophthalmicmacrolide anti-infectives, ophthalmic quinolone anti-infectives,ophthalmic sulfonamide anti-infectives, ophthalmic tetracyclineanti-infectives, ophthalmic anti-inflammatory agents, ophthalmiccorticosteroid anti-inflammatory agents, and ophthalmic nonsteroidalanti-inflammatory drugs (NSAIDs); psychotropic agents, such asantidepressants, heterocyclic antidepressants, monoamine oxidaseinhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs),tricyclic antidepressants, antimanics, antipsychotics, phenothiazineantipsychotics, anxiolytics, sedatives, and hypnotics, barbituratesedatives and hypnotics, benzodiazepine anxiolytics, sedatives, andhypnotics, and psychostimulants; respiratory agents, such asantitussives, bronchodilators, adrenergic agonist bronchodilators,antimuscarinic bronchodilators, expectorants, mucolytic agents,respiratory anti-inflammatory agents, and respiratory corticosteroidanti-inflammatory agents; toxicology agents, such as antidotes, heavymetal antagonists/chelating agents, substance abuse agents, deterrentsubstance abuse agents, and withdrawal substance abuse agents; minerals;and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D,vitamin E, and vitamin K.

Preferred classes of useful biologically active substances from theabove categories include: (1) nonsteroidal anti-inflammatory drugs(NSAIDs) analgesics, such as diclofenac, ibuprofen, ketoprofen, andnaproxen; (2) opiate agonist analgesics, such as codeine, fentanyl,hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin(ASA) (enteric coated ASA); (4) H₁-blocker antihistamines, such asclemastine and terfenadine; (5) H₂-blocker antihistamines, such ascimetidine, famotidine, nizadine, and ranitidine; (6) anti-infectiveagents, such as mupirocin; (7) antianaerobic anti-infectives, such aschloramphenicol and clindamycin; (8) antifungal antibioticanti-infectives, such as amphotericin b, clotrimazole, fluconazole, andketoconazole; (9) macrolide antibiotic anti-infectives, such asazithromycin and erythromycin; (10) miscellaneous β-lactam antibioticanti-infectives, such as aztreonam and imipenem; (11) penicillinantibiotic anti-infectives, such as nafcillin, oxacillin, penicillin G,and penicillin V; (12) quinolone antibiotic anti-infectives, such asciprofloxacin and norfloxacin; (13) tetracycline antibioticanti-infectives, such as doxycycline, minocycline, and tetracycline;(14) antituberculosis antimycobacterial anti-infectives such asisoniazid (INH), and rifampin; (15) antiprotozoal anti-infectives, suchas atovaquone and dapsone; (16) antimalarial antiprotozoalanti-infectives, such as chloroquine and pyrimethamine; (17)anti-retroviral anti-infectives, such as ritonavir and zidovudine; (18)antiviral anti-infective agents, such as acyclovir, ganciclovir,interferon alfa, and rimantadine; (19) alkylating antineoplastic agents,such as carboplatin and cisplatin; (20) nitrosourea alkylatingantineoplastic agents, such as carmustine (BCNU); (21) antimetaboliteantineoplastic agents, such as methotrexate; (22) pyrimidine analogantimetabolite antineoplastic agents, such as fluorouracil (5-FU) andgemcitabine; (23) hormonal antineoplastics, such as goserelin,leuprolide, and tamoxifen; (24) natural antineoplastics, such asaldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferonalfa, paclitaxel, and tretinoin (ATRA); (25) antibiotic naturalantineoplastics, such as bleomycin, dactinomycin, daunorubicin,doxorubicin, and mitomycin; (26) vinca alkaloid natural antineoplastics,such as vinblastine and vincristine; (27) autonomic agents, such asnicotine; (28) anticholinergic autonomic agents, such as benztropine andtrihexyphenidyl; (29) antimuscarinic anticholinergic autonomic agents,such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents,such as bromocriptine; (31) cholinergic agonist parasympathomimetics,such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics,such as pyridostigmine; (33) α-blocker sympatholytics, such as prazosin;(34) β-blocker sympatholytics, such as atenolol; (35) adrenergic agonistsympathomimetics, such as albuterol and dobutamine; (36) cardiovascularagents, such as aspirin (ASA) (enteric coated ASA); (37) β-blockerantianginals, such as atenolol and propranolol; (38) calcium-channelblocker antianginals, such as nifedipine and verapamil; (39) nitrateantianginals, such as isosorbide dinitrate (ISDN); (40) cardiacglycoside antiarrhythmics, such as digoxin; (41) class Iantiarrhythmics, such as lidocaine, mexiletine, phenytoin, procainamide,and quinidine; (42) class II antiarrhythmics, such as atenolol,metoprolol, propranolol, and timolol; (43) class III antiarrhythmics,such as amiodarone; (44) class IV antiarrhythmics, such as diltiazem andverapamil; (45) α-blocker antihypertensives, such as prazosin; (46)angiotensin-converting enzyme inhibitor (ACE inhibitor)antihypertensives, such as captopril and enalapril; (47) β-blockerantihypertensives, such as atenolol, metoprolol, nadolol, andpropanolol; (48) calcium-channel blocker antihypertensive agents, suchas diltiazem and nifedipine; (49) central-acting adrenergicantihypertensives, such as clonidine and methyldopa; (50) diurecticantihypertensive agents, such as amiloride, furosemide,hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheralvasodilator antihypertensives, such as hydralazine and minoxidil; (52)antilipemics, such as gemfibrozil and probucol; (53) bile acidsequestrant antilipemics, such as cholestyramine; (54) HMG-CoA reductaseinhibitor antilipemics, such as lovastatin and pravastatin; (55)inotropes, such as amrinone, dobutamine, and dopamine; (56) cardiacglycoside inotropes, such as digoxin; (57) thrombolytic agents, such asalteplase (TPA), anistreplase, streptokinase, and urokinase; (58)dermatological agents, such as colchicine, isotretinoin, methotrexate,minoxidil, tretinoin (ATRA); (59) dermatological corticosteroidanti-inflammatory agents, such as betamethasone and dexamethasone; (60)antifungal topical anti-infectives, such as amphotericin B,clotrimazole, miconazole, and nystatin; (61) antiviral topicalanti-infectives, such as acyclovir; (62) topical antineoplastics, suchas fluorouracil (5-FU); (63) electrolytic and renal agents, such aslactulose; (64) loop diuretics, such as furosemide; (65)potassium-sparing diuretics, such as triamterene; (66) thiazidediuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents,such as probenecid; (68) enzymes such as RNase and DNase; (69)thrombolytic enzymes, such as alteplase, anistreplase, streptokinase andurokinase; (70) antiemetics, such as prochlorperazine; (71) salicylategastrointestinal anti-inflammatory agents, such as sulfasalazine; (72)gastric acid-pump inhibitor anti-ulcer agents, such as omeprazole; (73)H₂-blocker anti-ulcer agents, such as cimetidine, famotidine,nizatidine, and ranitidine; (74) digestants, such as pancrelipase; (75)prokinetic agents, such as erythromycin; (76) opiate agonist intravenousanesthetics such as fentanyl; (77) hematopoietic antianemia agents, suchas erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78)coagulation agents, such as antihemophilic factors 1-10 (AHF 1-10); (79)anticoagulants, such as warfarin; (80) thrombolytic enzyme coagulationagents, such as alteplase, anistreplase, streptokinase and urokinase;(81) hormones and hormone modifiers, such as bromocriptine; (82)abortifacients, such as methotrexate; (83) antidiabetic agents, such asinsulin; (84) oral contraceptives, such as estrogen and progestin; (85)progestin contraceptives, such as levonorgestrel and norgestrel; (86)estrogens such as conjugated estrogens, diethylstilbestrol (DES),estrogen (estradiol, estrone, and estropipate); (87) fertility agents,such as clomiphene, human chorionic gonadotropin (HCG), and menotropins;(88) parathyroid agents such as calcitonin; (89) pituitary hormones,such as desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90)progestins, such as medroxyprogesterone, norethindrone, andprogesterone; (91) thyroid hormones, such as levothyroxine; (92)immunobiologic agents, such as interferon beta-lb and interferongamma-1b; (93) immunoglobulins, such as immune globulin IM, IMIG, IGIMand immune globulin IV, IVIG, IGIV; (94) amide local anesthetics, suchas lidocaine; (95) ester local anesthetics, such as benzocaine andprocaine; (96) musculoskeletal corticosteroid anti-inflammatory agents,such as beclomethasone, betamethasone, cortisone, dexamethasone,hydrocortisone, and prednisone; (97) musculoskeletal anti-inflammatoryimmunosuppressives, such as azathioprine, cyclophosphamide, andmethotrexate; (98) musculoskeletal nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, andnaproxen; (99) skeletal muscle relaxants, such as baclofen,cyclobenzaprine, and diazepam; (100) reverse neuromuscular blockerskeletal muscle relaxants, such as pyridostigmine; (101) neurologicalagents, such as nimodipine, riluzole, tacrine and ticlopidine; (102)anticonvulsants, such as carbamazepine, gabapentin, lamotrigine,phenytoin, and valproic acid; (103) barbiturate anticonvulsants, such asphenobarbital and primidone; (104) benzodiazepine anticonvulsants, suchas clonazepam, diazepam, and lorazepam; (105) anti-parkinsonian agents,such as bromocriptine, levodopa, carbidopa, and pergolide; (106)anti-vertigo agents, such as meclizine; (107) opiate agonists, such ascodeine, fentanyl, hydromorphone, methadone, and morphine; (108) opiateantagonists, such as naloxone; (109) β-blocker anti-glaucoma agents,such as timolol; (110) miotic anti-glaucoma agents, such as pilocarpine;(111) ophthalmic aminoglycoside anti-infectives, such as gentamicin,neomycin, and tobramycin; (112) ophthalmic quinolone anti-infectives,such as ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmiccorticosteroid anti-inflammatory agents, such as dexamethasone andprednisolone; (114) ophthalmic nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine,haloperidol, and risperidone; (116) benzodiazepine anxiolytics,sedatives and hypnotics, such as clonazepam, diazepam, lorazepam,oxazepam, and prazepam; (117) psychostimulants, such as methylphenidateand pemoline; (118) antitussives, such as codeine; (119)bronchodilators, such as theophylline; (120) adrenergic agonistbronchodilators, such as albuterol; (121) respiratory corticosteroidanti-inflammatory agents, such as dexamethasone; (122) antidotes, suchas flumazenil and naloxone; (123) heavy metal antagonists/chelatingagents, such as penicillamine; (124) deterrent substance abuse agents,such as disulfiram, naltrexone, and nicotine; (125) withdrawal substanceabuse agents, such as bromocriptine; (126) minerals, such as iron,calcium, and magnesium; (127) vitamin B compounds, such ascyanocobalamin (vitamin B₁₂) and niacin (vitamin B₃); (128) vitamin Ccompounds, such as ascorbic acid; and (129) vitamin D compounds, such ascalcitriol.

In addition to the foregoing, the following less common drugs may alsobe used: chlorhexidine; estradiol cypionate in oil; estradiol valeratein oil; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa;nafarelin; and somatropin.

Further, the following new drugs may also be used: recombinantbeta-glucan; bovine immunoglobulin concentrate; bovine superoxidedismutase; the formulation comprising fluorouracil, epinephrine, andbovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen; humananti-TAC antibody; recombinant human growth hormone (r-hGH); recombinanthuman hemoglobin (r-Hb); recombinant human mecasermin (r-IGF-1);recombinant interferon beta-1a; lenograstim (G-CSF); olanzapine;recombinant thyroid stimulating hormone (r-TSH); and topotecan.

Further still, the following intravenous products may be used: acyclovirsodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin;salmon calcitonin; carboplatin; carmustine; dactinomycin, daunorubicinHCl; docetaxel; doxorubicin HCl; epoetin alfa; etoposide (VP-16);fluorouracil (5-FU); ganciclovir sodium; gentamicin sulfate; interferonalfa; leuprolide acetate; meperidine HCl; methadone HCl; methotrexatesodium; paclitaxel; ranitidine HCl; vinblastin sulfate; and zidovudine(AZT).

Still further, the following listing of peptides, proteins, and otherlarge molecules may also be used, such as interleukins 1 through 18,including mutants and analogues; interferons α, β, and γ; luteinizinghormone releasing hormone (LHRH) and analogues, gonadatropin releasinghormone (GnRH), transforming growth factor-β (TGF-β); fibroblast growthfactor (FGF); tumor necrosis factor-α & β (TNF-α & β); nerve growthfactor (NGF); growth hormone releasing factor (GHRF); epidermal growthfactor (EGF); fibroblast growth factor homologous factor (FGFHF);hepatocyte growth factor (HGF); insulin growth factor (IGF);platelet-derived growth factor (PDGF); invasion inhibiting factor-2(IIF-2); bone morphogenetic proteins 1-7 (BMP 1-7); somatostatin;thymosin-α-1; γ-globulin; superoxide dismutase (SOD); and complementfactors.

Alternatively, the biologically active substance may be nucleic acidscomprised of nucleotides linked together into polynucleotide chains withbackbones consisting of alternating series of pentose sugars andphosphate residues. One way to avoid the complications of developingcell-based systems for delivering genes to patients in gene therapy isto deliver retroviral vectors directly to target cells. For example,this technique has been used to infect endothelial cells of blood vesselwalls. The polymers and compositions of the invention may be used fordirect delivery of such retroviral vectors and/or related geneticmaterials to other sites in vivo, for example, to the lungs to treatailments in the lungs, such as cystic fibrosis, or to treat tumors inany localized portion of the body.

Preferably, the biologically active substance is selected from the groupconsisting of peptides, polypeptides, proteins, amino acids,polysaccharides, growth factors, hormones, anti-angiogenesis factors,interferons or cytokines, antigenic materials, and pro-drugs. In aparticularly preferred embodiment, the biologically active substance isa therapeutic drug or pro-drug, most preferably a drug selected from thegroup consisting of chemotherapeutic agents and other anti-neoplasticssuch as paclitaxel, antibiotics, anti-virals, anti-fungals,anti-inflammatories, and anticoagulants, antigens useful for vaccineapplications or corresponding pro-drugs.

Various forms of the biologically active agents may be used. Theseinclude, without limitation, such forms as uncharged molecules,molecular complexes, salts, ethers, esters, amides, and the like, whichare biologically activated when implanted, injected or otherwise placedinto the body.

L in the polymer composition of the invention can be any divalentcycloaliphatic group so long as it does not interfere with thepolymerization or biodegradation reactions of the polymer of thecomposition. Specific examples of useful L groups include unsubstitutedand substituted cycloalkylene groups, such as cyclopentylene,2-methyl-cyclopentylene, cyclohexylene, 2-chlorocyclohexylene, and thelike; cycloalkenylene groups, such as cyclohexenylene; and cycloalkylenegroups having fused or bridged additional ring structures on one or moresides, such as tetralinylene, decalinylene, and norpinanylene; or thelike.

R″ in the polymer composition of the invention is an alkyl, alkoxy,aryl, aryloxy, heterocyclic or heterocycloxy residue. Examples of usefulalkyl R″ groups include methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl, —C₈H₁₇, and the like groups; alkyl substituted with anon-interfering substituent, such as a halogen group; correspondingalkoxy groups; and alkyl that is conjugated with a biologically activesubstance to form a pendant drug delivery system.

When R″ is alkyl or alkoxy, it preferably contains about 2 to about 20carbon atoms, even more preferably about 6 to about 15 carbon atoms.When R″ is aryl or the corresponding aryloxy group, it typicallycontains from about 5 to about 14 carbon atoms, preferably about 5 to 12carbon atoms and, optionally, can contain one or more rings that arefused to each other. Examples of particularly suitable aromatic groupsinclude phenyl, phenoxy, naphthyl, anthracenyl, phenanthrenyl and thelike.

When R″ is heterocyclic or heterocycloxy, it typically contains fromabout 5 to 14 ring atoms, preferably from about 5 to 12 ring atoms, andone or more heteroatoms. Examples of suitable heterocyclic groupsinclude furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole,2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole,isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole,1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole,1,2,5-oxatriazole, 1,3-oxathiole, 1,2-pyran, 1,4-pyran, 1,2-pyrone,1,4-pyrone, 1,2-dioxin-, 1,3-dioxin, pyridine, N-alkyl pyridinium,pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine,1,2,3-triazine, 1,2,4-oxazine, 1,3,2-oxazine, 1,3,5-oxazine,1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-oxathiazine,1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5,2-oxadiazine, azepine,oxepin, thiepin, 1,2,4-diazepine, indene, isoindene, benzofuran,isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine,2-isobenzazole, 1,4-pyrindine, pyrando[3,4-b]-pyrrole, isoindazole,indoxazine, benzoxazole, anthranil, 1,2-benzopyran, 1,2-benzopyrone,1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline,isoquinoline, 12,-benzodiazine, 1,3-benzodiazine, naphthpyridine,pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine, pyrido[4,3-b]pyridine,1,3,2-benzoxazine, 1,4,2-benzoxazine, 2,3,1-benzoxazine,3,1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole,xanthrene, acridine, purine, and the like. Preferably, when R″ isheterocyclic or heterocycloxy, it is selected from the group consistingof furan, pyridine, N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene,anthracene and purine rings.

In a particularly preferred embodiment, R″ is an alkyl group, an alkoxygroup, a phenyl group, a phenoxy group, or a heterocycloxy group and,even more preferably, an alkoxy group having from 1 to 10 carbon atoms.Most preferably, R″ is an ethoxy or hexyloxy group.

Alternatively, the side chain R″ can be a biologically active substancependently attached to the polymer backbone, for example by ionic orcovalent bonding. In this pendant system, the biologically activesubstance is released as the bond connecting R″ with the phosphorousatom is cleaved under physiological conditions.

The number “n” can vary greatly depending on the biodegradability andthe release characteristics desired in the polymer, but typically variesbetween about 5 and 1,000. Preferably, n is from about 5 to about 500and, most preferably, from about 5 to about 200.

The molecular weight of the polymer used in the composition of theinvention can vary widely, but must remain low enough for the polymer tomaintain its flowable or flexible state. For example, weight-averagemolecular weights (Mw) typically vary from about 2,000 to about 400,000daltons, preferably from about 2,000 to about 200,000 daltons and, mostpreferably, from about 2,000 to 50,000 daltons. Number-average molecularweight (Mn) can also vary widely, but generally fall in the range ofabout 1,000 to about 200,000 daltons, preferably from about 1,000 toabout 100,000 daltons and, most preferably, from about 1,000 to about25,000 daltons.

Biodegradable polymers differ from non-biodegradable polymers in thatthey can be degraded during in vivo therapy. This generally involvesbreaking down the polymer into its monomeric subunits. In principle, theultimate hydrolytic breakdown products of the polymer used in theinvention are a cycloaliphatic diol, an aliphatic alcohol and phosphate.All of these degradation products are potentially non-toxic. However,the intermediate oligomeric products of the hydrolysis may havedifferent properties. Thus, the toxicology of a biodegradable polymerintended for injection or placing totally or partially within the body,even one synthesized from apparently innocuous monomeric structures, istypically determined after one or more toxicity analyses.

There are many different ways of testing for toxicity and/orbiocompatibility known to those of ordinary skill in the art. A typicalin vitro toxicity assay, however, would be performed with live carcinomacells, such as GT3TKB tumor cells, in the following manner:

Two hundred microliters of various concentrations of the degradedpolymer products are placed in 96-well tissue culture plates seeded withhuman gastric carcinoma cells (GT3TKB) at 10⁴/well density. The degradedpolymer products are incubated with the GT3TKB cells for 48 hours. Theresults of the assay can be plotted as % relative growth vs.concentration of degraded polymer in the tissue-culture well.

Polymers for use in medical applications, such as drug delivery systems,can also be evaluated by well-known in vivo biocompatibility tests, suchas by subcutaneous implantation or injection in rats to confirm that thesystems hydrolyze without significant levels of irritation orinflammation at the insertion site.

The biodegradable polymer used in the invention is preferablysufficiently pure to be biocompatible itself and remains biocompatibleupon biodegradation. By “biocompatible”, it is meant that thebiodegradation products or the polymer itself are non-toxic and resultin only minimal tissue irritation when injected or placed into intimatecontact with vasculated tissues. The requirement for biocompatibility ismore easily accomplished because the presence of an organic solvent isnot required in the polymer composition of the invention.

However, the polymer used in the invention is preferably soluble in oneor more common organic solvents for ease of synthesis, purification andhandling. Common organic solvents include such solvents as ethanol,chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide, and dimethylsulfoxide. The polymer ispreferably soluble in at least one of the above solvents.

The polymer of the invention can also comprise additional biocompatiblemonomeric units so long as they do not interfere with the biodegradablecharacteristics and the desirable flow characteristics of the invention.Such additional monomeric units may offer even greater flexibility indesigning the precise release profile desired for targeted drug deliveryor the precise rate of biodegradability desired for other applications.When such additional monomeric units are used, however, they should beused in small enough amounts to insure the production of a biodegradablecopolymer having the desired physical characteristics, such asviscosity, flowability, flexibility or morphology.

Examples of such additional biocompatible monomers include the recurringunits found in other poly(phosphoesters), poly(lactides),poly(glycolides), poly(caprolactones), poly~anhydrides)J poly(amides),poly(urethanes), poly(esteramides), poly(orthoesters), poly(dioxanones),poly(acetals), poly(ketals), poly(carbonates), poly(orthocarbonates),poly(phosphazenes), poly(hydroxybutyrates), poly(hydroxyvalerates),poly(alkylene oxalates), poly(alkylene succinates), poly(malic acids),poly(amino acids), poly(vinylpyrrolidone), poly(ethylene glycol),poly(hydroxycellulose), chitin, chitosan, and copolymers, terpolymers,or combinations or mixtures of the above materials.

When additional monomeric units are used, those which have a lowerdegree of crystallization and are more hydrophobic are preferred.Especially preferred recurring units with the desired physicalcharacteristics are those derived from poly(lactides),poly(caprolactones), and copolymers of these with glycolide, in whichthere are more amorphous regions.

Synthesis of Poly(cycloaliphatic phosphoester) Polymers

The most common general reaction in preparing poly-(phosphates) is adehydrochlorination between a phosphorodichloridate and a diol accordingto the following equation:

Most poly(phosphonates) are also obtained by condensation betweenappropriately substituted dichlorides and diols.

Poly(phosphites) have been prepared from glycols in a two-stepcondensation reaction. A 20% molar excess of a dimethylphosphite is usedto react with the glycol, followed by the removal of themethoxyphosphonyl end groups in the oligomers by high temperature.

An advantage of melt polycondensation is that it avoids the use ofsolvents and large amounts of other additives, thus making purificationmore straightforward. It can also provide polymers of reasonably highmolecular weight. Somewhat rigorous conditions, however, are oftenrequired and can lead to chain acidolysis (or hydrolysis if water ispresent). Unwanted, thermally-induced side reactions, such ascrosslinking reactions, can also occur if the polymer backbone issusceptible to hydrogen atom abstraction or oxidation with subsequentmacroradical recombination.

To minimize these side reactions, the polymerization can also be carriedout in solution. Solution polycondensation requires that both theprepolymer and the phosphorus component be soluble in a common solvent.Typically, a chlorinated organic solvent is used, such as chloroform,dichloromethane, or dichloroethane.

The solution polymerization is preferably run in the presence ofequimolar amounts of the reactants and a stoichiometric amount of anacid acceptor, usually a tertiary amine such as pyridine ortriethylamine. The product is then typically isolated from the solutionby precipitation in a non-solvent and purified to remove thehydrochloride salt by conventional techniques known to those of ordinaryskill in the art, such as by washing with an aqueous acidic solution,e.g., dilute HCl.

Reaction times tend to be longer with solution polymerization than withmelt polymerization. However, because overall milder reaction conditionscan be used, side reactions are minimized, and more sensitive functionalgroups can be incorporated into the polymer. Moreover, attainment ofundesirably high molecular weights is less likely with solutionpolymerization.

Interfacial polycondensation can be used when high reaction rates aredesired. The mild conditions used minimize side reactions, and there isno need for stoichiometric equivalence between the diol and dichloridatestarting materials as in solution methods. However, hydrolysis of theacid chloride may occur in the alkaline aqueous phase. Sensitivedichloridates that have some solubility in water are generally subjectto hydrolysis rather than polymerization. Phase transfer catalysts, suchas crown ethers or tertiary ammonium chloride, can be used to bring theionized diol to the interface to facilitate the polycondensationreaction. The yield and molecular weight of the resulting polymer afterinterfacial polycondensation are affected by reaction time, molar ratioof the monomers, volume ratio of the immiscible solvents, the type ofacid acceptor, and the type and concentration of the phase transfercatalyst.

In a preferred embodiment of the invention, the biodegradable polymer offormula I is made by a process comprising the step of reacting a diolhaving the formula:

HO—R—L—R′—OH

wherein R, R′ and L are as defined above, with a phosphorodihalidate offormula II:

where “halo” is Br, Cl or I, and R− is as defined above, to form thepolymer of formula I. The diol HO—R—L—R′—OH can be prepared by standardprocedures of chemistry, and many such compounds are available on acommercial basis.

When either R or R′ is a biologically active substance, the biologicallyactive substance is preferably itself a diol, for example, a steroidsuch as estradiol. Alternatively, the biologically active substance canbe a diamino compound that is reacted with the carboxyl group of acarboxylic acid to produce terminal hydroxyl groups that can be used toform the poly(phosphoester) structure.

The purpose of the polymerization reaction is to form a polymercomprising (i) cycloaliphatic recurring units and (ii) phosphoesterrecurring units. The result can be a homopolymer, a relativelyhomogeneous copolymer, or a block copolymer that has a somewhatheterogeneous microcrystalline structure. Any one of these threeembodiments is well-suited for use as a controlled release medium.

The process used to make the polymers used in the invention can takeplace at widely varying temperatures, depending upon whether a solventis used and, if so, which one; the molecular weight desired; thesolubility desired; the susceptibility of the reactants to form sidereactions; and the presence of a catalyst. Preferably, however, theprocess takes place at a temperature ranging from about 0 to about +235°C. for melt conditions. Somewhat lower temperatures, e.g., from about−50 to about 100° C., may be possible with solution polymerization orwith the use of either a cationic or anionic catalyst.

The time required for the process can also vary widely, depending uponthe type of reaction being used, the molecular weight desired and, ingeneral, the need to use more or less rigorous conditions for thereaction to proceed to the desired degree of completion. Typically,however, the process takes place during a time between about 30 minutesand 4 days.

While the process may be in bulk, in solution, by interfacialpolycondensation, or any other convenient method of polymerization,preferably, the process takes place under solution conditions.Particularly useful solvents include methylene chloride, chloroform,tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide, toluene, or anyof a wide variety of other inert organic solvents.

Particularly when solution polymerization reaction is used, an acidacceptor is advantageously present during the polymerization reaction. Aparticularly suitable class of acid acceptor comprises tertiary amines,such as pyridine, trimethylamine, triethylamine, substituted anilinesand substituted aminopyridines. The most preferred acid acceptor is thesubstituted aminopyridine 4-dimethylaminopyridine (“DMAP”).

The addition sequence for solution polymerization can vary significantlydepending upon the relative reactivities of the diol; thephosphorodihalidate of formula II; the purity of these reactants; thetemperature at which the polymerization reaction is preformed; thedegree of agitation used in the polymerization reaction; and the like.Preferably, however, the diol is combined with a solvent and an acidacceptor, and then the phosphorodihalidate is added slowly. For example,a solution of the phosphorodihalidate in a solvent may be trickled in oradded dropwise to the chilled reaction mixture of diol, solvent and acidacceptor, to control the rate of the polymerization reaction.

The polymer of formula I is isolated from the reaction mixture byconventional techniques, such as by precipitating out, extraction withan immiscible solvent, evaporation, filtration, crystallization and thelike. Typically, however, the polymer of formula I is both isolated andpurified by quenching a solution of the polymer with a non-solvent or apartial solvent, such as diethyl ether or petroleum ether.

Biodegradability and Release Characteristics

The polymer of formula I is usually characterized by a biodegradationrate that is controlled at least in part as a function of hydrolysis ofthe phosphoester bond of the polymer. Other factors are also important.For example, the lifetime of a biodegradable polymer in vivo alsodepends upon its molecular weight, crystallinity, biostability, and thedegree of crosslinking. In general, the greater the molecular weight,the higher the degree of crystallinity, and the greater thebiostability, the slower biodegradation will be. In addition, the rateof degradation of the polymer can be further controlled by choosing aside chain of differing lengths. Accordingly, degradation times can verywidely, preferably from less than a day to several months.

Accordingly, the structure of the side chain can influence the releasebehavior of compositions comprising a biologically active substance. Forexample, it is expected that conversion of the phosphate side chain to amore lipophilic, more hydrophobic or bulky group would slow down thedegradation process. Thus, release is usually faster from polymercompositions with a small aliphatic group side chain than with a bulkyaromatic side chain. Moreover, when R and/or R′ in the backbone portionof formula I is itself a biologically active substance, the release rateof the biologically active substance in vivo is primarily governed bythe rate of biodegradation. When the biologically active substance to bereleased is conjugated to the phosphorus side chain R″ to form a pendantdrug delivery system, the release profile is governed to a significantdegree by the lability of the phosphorous-R″ bond.

The mechanical properties of the polymer are also important with respectto the flowability or flexibility of the composition containing thepolymer. For example, the glass transition temperature is preferably lowenough to keep the composition of the invention flowable at bodytemperature. Even more preferably, the glass transition temperature ofthe polymer used in the invention is about 0 to about 37° C. and, mostpreferably, from about 0 to about 25° C.

Polymer Compositions

The polymer composition of the invention may be a flexible or flowablematerial. By “flowable” is meant the ability to assume, over time, theshape of the space containing it at body temperature. This includes, forexample, liquid compositions that are capable of being sprayed into asite; injected with a manually operated syringe fitted with, forexample, a 23-gauge needle; or delivered through a catheter.

Also included by the term “flowable”, however, are highly viscous,“gel-like” materials at room temperature that may be delivered to thedesired site by pouring, squeezing from a tube, or being injected withany one of the commercially available power injection devices thatprovide injection pressures greater than would be exerted by manualmeans alone for highly viscous, but still flowable, materials. When thepolymer used is itself flowable, the polymer composition of theinvention, even when viscous, need not include a biocompatible solventto be flowable, although trace or residual amounts of biocompatiblesolvents may still be present. The viscosity of the polymer can beadjusted by the molecular weight of the polymer, as well as by mixingthe cis- and trans- isomers of the cyclohexane dimethanol in thebackbone of the polymer.

Even without the presence of a biologically active substance, thepolymer composition of the invention can be used for a variety ofmedical applications. For example, it can be injected to form, afterinjection, a temporary biomechanical barrier to coat or encapsulateinternal organs or tissues, such as the barriers used to preventadhesions after abdominal surgery. The polymer composition of theinvention can also be used to produce bone waxes and fillers forrepairing injuries to bone or connective tissue, temporary internal“bandages” to prevent further internal injury or promote internal woundhealing, or coatings for solid implantable devices.

The biodegradable composition can even be injected subdermally to buildup tissue or to fill in defects. The injected polymer composition willslowly biodegrade within the body and allow natural tissue to grow andreplace the polymer matrix as it disappears. Thus, when the material isinjected into a soft-tissue defect, it will fill that defect and providea scaffold for natural collagen tissue to grow. This collagen tissuewill gradually replace the biodegradable polymer. However, preferably,the polymer composition of the invention does comprise a biologicallyactive substance and provides controllable and effective release of thebiologically active substance over time, even in the case of largebio-macromolecules. Thus, in a preferred embodiment, the biodegradablepolymer composition comprises both:

(a) at least one biologically active substance and

(b) the polymer having the recurring monomeric units shown in formula Iwhere R, R′ , L, R″ and n are as defined above.

The biologically active substances are used in amounts that aretherapeutically effective, which varies widely depending largely on theparticular biologically active substance being used. The amount ofbiologically active substance incorporated into the composition alsodepends upon the desired release profile, the concentration of thesubstance required for a biological effect, and the length of time thatthe biologically active substance has to be released for treatment.Preferably, the biologically active substance can be easily blended withthe polymer matrix of the invention at different loading levels, at roomtemperature and without the need for an organic solvent. However, it isalso possible to use a solvent during the blending process for morerapid or complete blending, and then evaporate off the solvent whenblending is complete.

There is no critical upper limit on the amount of biologically activesubstance incorporated except for that of an acceptable solution ordispersion viscosity to maintain the physical characteristics desiredfor the composition. The lower limit of the substance incorporated intothe delivery system is dependent upon the activity of the drug and thelength of time needed for treatment. Thus, the amount of thebiologically active substance should not be so small that it fails toproduce the desired physiological effect, nor so large that thebiologically active substance is released in an uncontrollable manner.

Typically, within these limits, amounts of the biologically activesubstance from about 1% up to about 65% can be incorporated into thepresent delivery systems. However, lesser amounts may be used to achieveefficacious levels of treatment for biologically active substances thatare particularly potent.

In addition, the polymer composition of the invention can also compriseblends of the polymer of the invention with other biocompatible polymersor copolymers, so long as the additional polymers or copolymers do notinterfere undesirably with the biodegradable or mechanicalcharacteristics of the composition. Blends of the polymer of theinvention with such other polymers may offer even greater flexibility indesigning the precise release profile desired for targeted drug deliveryor the precise rate of biodegradability desired. Examples of suchadditional biocompatible polymers include other poly(phosphoesters),poly(carbonates), polytesters), poly(orthoesters), poly(phosphazenes),poly(amides), poly(urethanes), poly(imino-carbonates), andpoly(anhydrides).

Pharmaceutically acceptable polymeric carriers may also comprise a widerange of additional materials. Without being limited thereto, suchmaterials may include diluents, binders and adhesives, lubricants,disintegrants, colorants, bulking agents, flavorings, sweeteners, andmiscellaneous materials such as buffers and adsorbents, in order toprepare a particular medicated composition, with the condition that noneof these additional materials will interfere with the biocompatibility,biodegradability and flowability or flexibility of the polymercompositions of the invention.

For delivery of a biologically active substance, the biologically activesubstance is added to the polymer composition. The biologically activesubstance is either dissolved to form a homogeneous solution ofreasonably constant concentration in the polymer composition, ordispersed to form a suspension or dispersion within the polymercomposition at a desired level of “loading” (grams of biologicallyactive substance per grams of total composition including thebiologically active substance, usually expressed as a percentage).

While it is possible that the biodegradable polymer or the biologicallyactive agent may be dissolved in a small quantity of a solvent that isnon-toxic to more efficiently produce a homogeneous, monolithicdistribution or a fine dispersion of the biologically active agent inthe flexible or flowable composition, it is an advantage of theinvention that, in a preferred embodiment, no solvent is needed to forma flowable composition. Moreover, the use of solvents is preferablyavoided because, once a polymer composition containing solvent is placedtotally or partially within the body, the solvent dissipates or diffusesaway from the polymer and must be processed and eliminated by the body,placing an extra burden on the body's clearance ability at a time whenillness or injury may have already deleteriously affected it.

However, when a solvent is used to facilitate mixing or to maintain theflowability of the polymer composition of the invention, it should benon-toxic, otherwise biocompatible, and should be used in minimalamounts. Solvents that are toxic clearly should not be used in anymaterial to be placed even partially within a living body. Such asolvent also must not cause tissue irritation or necrosis at the site ofadministration.

Examples of suitable biocompatible solvents, when used, includeN-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol,acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam,dimethyl-sulfoxide, oleic acid, or 1-dodecylazacycloheptan-2-one.Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, and acetone because of their solvating ability andtheir biocompatibility.

Flowable or Flexible Delivery Systems

In its simplest form, a biodegradable therapeutic agent delivery systemconsists of a solution or dispersion of a biologically active substancein a polymer matrix having an unstable (biodegradable) bond incorporatedinto the polymer backbone. Cleavage of the bond converts awater-insoluble polymer into water-soluble, low molecular weight polymerfragments that can be excreted from the body.

The biologically active substance is typically released from thepolymeric matrix at least as quickly as the matrix biodegrades in vivo.With some biologically active substances, the substance will be releasedonly after the polymer has been degraded to a point where anon-diffusing substance has been exposed to bodily fluids. As thepolymer begins to degrade, the biologically active substance that wascompletely surrounded by the polymer matrix begins to be liberated.However, with this mechanism, a long peptide chain that is physicallyentangled in a rigid solid implant structure may tend to degrade alongwith the matrix and break off from the remainder of the peptide chain,thereby releasing incomplete fragments of molecules.

With the polymer compositions of the invention, however, the polymerwill typically degrade after the peptide or protein has been released inpart. In a particularly preferred mechanism, when a peptide chain isbeing released from the composition of the invention, the compositionremains flexible and allows a large-molecule protein to, at leastpartially, diffuse through the polymeric matrix prior to its own or thepolymer's biodegradation.

The initial release rate of proteins from the compositions is thereforegenerally diffusion-controlled through channels in the matrix structure,the rate of which is inversely proportional to the molecular weight ofthe protein. Once polymer degradation begins, however, the proteinremaining in the matrix may also be released by the forces of erosion.

The biodegradable amorphous matrices of the invention typically containpolymer chains that are associated with other chains. These associationscan be created by a simple entanglement of polymer chains within thematrix, as opposed to hydrogen bonding or Van der Vaals interactions orbetween crystalline regions of the polymer or interactions that areionic in nature. Alternatively, the synthesis of block copolymers or theblending of two different polymers can be used to create viscous,“putty-like” materials with a wide variation in physical and mechanicalproperties.

When the biologically active substance is a protein, interactionsbetween specific proteins and the polymeric materials often also affectthe characteristics of the composition. Important factors include:

(i) the molecular weight of the protein, which is an important parameterwith regard to diffusion characteristics;

(ii) the isoelectric point of the protein, which governs charge-chargeinteractions;

(iii) the presence of cysteines on the protein, which may participate inthe formation of intermolecular disulfide bonds;

(iv) the primary amino acid sequence of the protein, which may besusceptible to chemical modification in association with a polymericmaterial;

(v) the presence or absence of carbohydrates on the protein, which mayenhance or prevent interaction with polymeric materials;

(vi) the relative hydrophobicity of a protein, which can interact withhydrophobic sites on a polymer; and

(vii) the heterogeneity of the protein, which often exists when proteinsare produced by recombinant methods.

In a particularly preferred embodiment, the composition of the inventionis sufficiently flowable to be injected into the body. It isparticularly important that the injected composition result in minimaltissue irritation after injection or otherwise being placed into directcontact with vasculated tissues.

The biologically active substance of the composition and the polymer ofthe invention may form a homogeneous matrix, or the biologically activesubstance may be encapsulated in some way within the polymer. Forexample, the biologically active substance may be first encapsulated ina microsphere and then combined with the polymer in such a way that atleast a portion of the microsphere structure is maintained.Alternatively, the biologically active substance may be sufficientlyimmiscible in the polymer of the invention that it is dispersed as smalldroplets, rather than being dissolved, in the polymer. Either form isacceptable, but it is preferred that, regardless of the homogeneity ofthe composition, a significant portion of the biologically activesubstance is released in vivo prior to the biodegradation of the polymerby hydrolysis of the phosphoester bond.

In one embodiment, the polymer composition of the invention is used toform a soft, drug-delivery “depot” that can be administered as a liquid,for example, by injection, but which remains sufficiently viscous tomaintain the drug within the localized area around the injection site.The degradation time of the depot so formed can be varied from severaldays to a few years, depending upon the polymer selected and itsmolecular weight. By using a polymer composition in flowable form, eventhe need to make an incision can be eliminated. In any event, theflexible or flowable delivery “depot” will adjust to the shape of thespace it occupies within the body with a minimum of trauma tosurrounding tissues.

The flexible or flowable polymer composition of the invention can beplaced anywhere within the body, including soft tissue such as muscle orfat; hard tissue such as bone or cartilage; a cavity such as theperiodontal, oral, vaginal, rectal or nasal cavity; or a pocket such asa periodontal pocket or the cul-de-sac of the eye. The composition mayalso be sprayed onto or poured into open wounds or used as a sitedelivery system during surgery.

When flowable, the composition of the invention can be injected intodeeper wounds, such as burn wounds, to prevent the formation of deepscars. The composition can also be used to act as a temporary barrier inpreventing the direct adhesion of different types of tissue to eachother, for example, after abdominal surgery, due to its ability toencapsulate tissues, organs and prosthetic devices.

In gene therapy, the flexible or flowable composition of the inventionmay be useful for providing a means for delivering genes to patientswithout involving a cell-based system. In particular, the composition ofthe invention may be injected into sites that would otherwise beinaccessible for direct delivery of gene vectors. In addition, dependingupon the need for continued gene therapy, the sustained releasecapability of the biologically active substance from the composition ofthe invention would eliminate the need for repeated invasive proceduresto re-introduce the gene vector to the involved site.

In orthopedic applications, the flowable or flexible composition of theinvention may be useful for repairing bone defects and connective tissueinjuries. For example, the biodegradable composition can be loaded withbone morphogenetic proteins to form a bone graft useful for even largesegmental defects, when the bone can be immobilized and supported. Thecomposition can also be injected into an appropriate orthopedic space tofacilitate cell adhesion and proliferation before the polymeric matrixdegrades to non-toxic residues.

Once injected, the polymer composition of the invention should remain inat least partial contact with a biological fluid, such as blood,internal organ secretions, mucous membranes, cerebrospinal fluid and thelike. For drug-delivery systems, the implanted or injected compositionwill release the biologically active substance contained within itsmatrix at a controlled rate until the substance is depleted, followingthe general rules for diffusion or dissolution of a biologically activesubstance from a biodegradable polymeric matrix.

The following examples are illustrative of preferred embodiments of theinvention and are not to be construed as limiting the invention thereto.All polymer molecular weights are average molecular weights. Allpercentages are based on the percent by weight of the final deliverysystem or formulation being prepared, unless otherwise indicated, andall totals equal 100% by weight.

EXAMPLES Example 1

Synthesis of the Poly(phosphoester) P(trans-CHDM-HOP)

Under an argon stream, 10 g of trans-1,4-cyclohexane dimethanol (CHDM),1.794 g of 4-dimethylaminopyridine (DMAP), 15.25 ml (14.03 g) ofN-methyl morpholine (NMM), and 50 ml of methylene chloride, weretransferred into a 250 ml flask equipped with a funnel. The solution inthe flask was cooled down to −15° C. with stirring, and a solution of15.19 g of hexyl phosphorodichloridate (HOP) in 30 ml of methylenechloride was added through the funnel. The temperature of the reactionmixture was raised to the boiling point gradually and maintained atreflux temperature overnight.

The reaction mixture was filtered, and the filtrate was evaporated todryness. The residue was re-dissolved in 100 ml of chloroform. Thissolution was washed with 0.1 M solution of a mixture of HCl and NaCl,dried over anhydrous Na₂SO₄, and quenched into 500 ml of ether. Theresulting flowable precipitate was collected and dried under vacuum toform a clear pale yellow gel-like polymer with the flow characteristicsof a viscous syrup. The yield for this polymer was 70-80%. The structureof P(trans-CHDM-HOP) was ascertained by ³¹P-NMR and ¹H-NMR spectra, asshown in FIG. 1, and by FT-IR spectra. The molecular weights (Mw=8584;Mn=3076) were determined by gel permeation chromatography (GPC), asshown in FIG. 2, using polystyrene as a calibration standard.

Example 2

Synthesis of the Poly(Phosphoester) P(cis & trans-CHDM-HOP)

Poly(phosphoester) P(cis/trans-l1,4-cyclohexane-dimethanol hexylphosphate) was prepared by following the procedure described above inExample 1 except that a mixture of cis- andtrans-1,4-cyclohexanedimethanol was used as the starting material. Asexpected, the product cis-/trans-P(CHDM-HOP) was less viscous than thetransisomer obtained in Example 1.

Example 3

Synthesis of Low Molecular Weight P(CHDM-HOP)

Under an argon stream, 10 g of trans-1,4-cyclohexane dimethanol (CHDM),15.25 mL (14.03 g) of N-methyl morpholine (NMM), and 50 mL of methylenechloride were transferred into a 250 mL flash equipped with a funnel.The solution in the flask was cooled down to −40° C. with stirring. Asolution of 15.19 g of hexyl phosphoro dichloridate (HOP) in 20 mL ofmethylene chloride was added through the funnel, and an additional 10 mLof methylene chloride was used to flush through the funnel. The mixturewas then brought up to room temperature gradually and kept stirring forfour hours.

The reaction mixture was filtered, and the filtrate was evaporated todryness. The residue was re-dissolved in 100 ml of chloroform. Thissolution was washed with 0.5 M mixture of HCl-NaCl solution, washed withsaturated NaCl solution, dried over anhydrous Na₂SO₄, and quenched intoa 1:5 ether-petroleum mixture. The resulting oily precipitate wascollected and dried under vacuum to form a clear, pale yellow viscousmaterial. The structure of the product was confirmed by ¹H-NMR, ³¹P-NMRand FT-IR spectra.

Example 4

Synthesis of the Poly(phosphoester) P(trans-CHDM-BOP)

Under an argon stream, 10 g of trans-1,4-cyclohexane dimethanol (CHDM),0.424 g (5%) of 4-dimethylamino-pyridine (DMAP), 15.25 mL (14.03 g) ofN-methyl morpholine (NMM) and 50 mL of methylene chloride weretransferred into a 250 mL flask equipped with a funnel. The solution inthe flask was cooled down to −40° C. with stirring. A solution of 13.24g of butyl phosphoro-dichloridate (BOP) in 20 mL of methylene chloridewas added through the funnel, with an additional 10 mL of methylenechloride being used to flush through the funnel. The mixture was heatedto the boiling point gradually, and kept refluxing for four hours. Thereaction mixture was filtered, and the filtrate was evaporated todryness, taking care to keep the temperature below 60° C. The residuewas redissolved in 100 mL of chloroform. The solution formed was washedwith 0.5 M of HCl-NaCl solution and saturated NaCl solution, dried overanhydrous Na₂SO₄, and quenched into a 1:5 ether-petroleum mixture. Theresulting oily precipitate was collected and dried under vacuum toproduce a clear, pale yellow viscous material.

Example 5

Synthesis of the Poly(phosphoester) P(trans-CHDM-EOP)

The polymer p(CHDM-EOP) was prepared by the method of Example 1 using,as starting materials, trans-1,4-cyclohexane dimethanol (CHDM) and ethylphosphoro-dichloridate (EOP).

Example 6

Rheological Properties of P(trans-CHDM-HOP)

P(trans-CHDM-HOP) remained in a flowable gel-like state at roomtemperature. The polymer exhibited a steady viscosity of 327Pa·s at 25°C. (shown in FIG. 3B), and a flowing active energy of 67.5 KJ/mol (shownin FIG. 3A).

Example 7

In Vitro Cytotoxicity of P(trans-CHDM-HOP)

Cover slips were coated with P(trans-CHDM-HOP) by a spin coating method.The coated coverslips were then dried and sterilized by UV irradiationovernight under a hood. A P(trans-CHDM-HOP)-coated cover slip was placedat the bottom of each well of a 6-well plate. 5×10⁵ HEK293 (humanembryonic kidney) cells were plated into each well and cultured for 72hours at 37° C. The resulting cell morphology was examined, using tissueculture polystyrene (TCPS) as a positive control. The cells growing onthe P(CHDM-HOP) surface proliferated at a slightly slower rate. However,the morphology of cells grown on the polymer surface was similar to themorphology of cells grown on the TCPS surface. See FIG. 4A for themorphology of HEK293 cells grown on the polymer surface and FIG. 4B forthe morphology of HEK293 cells grown on a TCPS surface, both after 72hours of incubation.

Example 8

In Vitro Degradation of P(CHDM-Alkyl Phosphates)

Each of the following poly(phosphate)s was prepared as described above:

TABLE I Polymer Side Chain P(CHDM-HOP) —O-hexyl group P(CHDM-BOP)—O-butyl group P(CHDM-EOP) —O-ethyl group

A sample of 50 mg of each polymer was incubated in 5 mL of 0.1 M, pH 7.4phosphate buffer saline (PBS) at 37° C. At various points in time, thesupernatant was poured out, and the polymer samples were washed threetimes with distilled water. The polymer samples were then extracted withchloroform, and the chloroform solution was evaporated to dryness. Theresidue was analyzed for weight loss by comparing with the original 50mg sample. FIG. 5 graphically represents the effect of the side chainstructure on the in vitro degradation rate of poly(phosphates) in PBS.

Example 9 In Vitro Release Profile of Protein by P(CHDM-HOP)

The polymer P(CHDM-HOP) was blended with the protein FITC-BSA (bovineserum albumin, a protein, tagged with the fluorescent label FITC;“FITC-BSA”) at a 2:1 (w/w) ratio (33% loading). Measured amounts (66 mgor 104 mg) of the polymer-protein blend were placed into 10 ml of PBS(0.1M, pH 7.4), a phosphate buffer. At regular intervals (roughly everyday), the samples were centrifuged, the supernatant buffer was removedand subjected to absorption spectroscopy (501 nm), and fresh amounts ofbuffer were added to the samples. The resulting release curve, plottingthe cumulative percentage of FITC-BSA released versus time, isgraphically represented in FIG. 6. The loading level of the protein inboth cases was 33 weight %.

Example 10

In Vitro Protein Release Profile At Various Loading Levels

FITC-BSA was blended with P(CHDM-HOP) at different loading levels (1%,10% and 30%) at room temperature until the mixture formed a homogenouspaste. 60 mg of the protein-loaded polymer paste was placed in 6 mL of0.1 M phosphate buffer and constantly shaken at 37° C. At various timepoints, samples were centrifuged, and the supernatant was replaced withfresh buffer. The released FITC-BSA in the supernatant was measured byUV spectrophotometry at 501 nm. FIG. 7 graphically represents the invitro release kinetics of FITC-BSA as a function of loading level.

Example 11

Effect of Side Chain Structure on In Vitro Protein Release Kinetics ofFITC-BSA

The following three polymers were prepared as described above:

P(CHDM-EOP)

P(CHDM-BOP) and

P(CHDM-HOP)

FITC-BSA was blended with each polymer at a 10% loading level at roomtemperature to form a homogenous paste. 60 mg of the protein-loadedpolymer paste was placed in 6 mL of 0.1 M phosphate buffer with constantshaking at 37° C. At various time points, samples were centrifuged, andthe supernatant was replaced with fresh buffer. The released FITC-BSA inthe supernatant was measured by UV spectrophotometry at 501 nm. FIG. 8graphically represents the in vitro effect of side chain variations onthe protein release kinetics of FITC-BSA at 10% loading level.

Example 12

In Vitro Small Molecular Weight Drug Release from P(CHDM-HOP)

A P(CHDM-HOP) paste containing doxorubicin, cisplatin, or5-fluorouracil, was prepared by blending 100 mg of P(CHDM-HOP) with 1 mgof the desired drug at room temperature, respectively. An aliquot of 60mg of the drug-loaded paste was placed in 6 mL of 0.1 M phosphate bufferat 37° C. with constant shaking, with three samples being done for eachdrug being tested. At various time points, the supernatant was replacedwith fresh buffer solution. The levels of doxorubicin and 5-fluorouracilin the supernatant were quantified by UV spectrophotometry at 484 nm and280 nm, respectively. The cisplatin level was measured with an atomicabsorbance spectrophotometer. FIG. 9 shows the release of these lowmolecular weight drugs from P(CHDM-HOP).

Example 13

In Vitro Simultaneous Release Profile of Doxorubicin and Cisplatin fromP(CHDM-HOP)

A paste was made by blending 300 mg of P(CHDM-HOP) with 6 mg ofdoxorubicin and 6 mg of cisplatin at room temperature to form a uniformdispersion. A sample of 100 mg of the paste was incubated in 10 mL ofphosphate buffer (pH 7.4) at 37° C. with shaking. At different timepoints, samples were centrifuged, 9 mL of the supernatant were withdrawnand replaced with fresh buffer. The withdrawn supernatant was assayedspectrophotometrically at 484 nm to determine the amount of doxorubicinreleased into the withdrawn supernatant, and the cisplatin release wasmeasured by atomic absorbance spectrophotometer. FIG. 10 graphicallyrepresents the simultaneous release of cisplatin and doxorubicin fromP(CHDM-HOP).

Example 14

In Vitro Interleukin-2 Release from P(CHDM-HOP)

A paste was prepared by blending, with a spatula, 330 mg of P(CHDM-HOP)with 3 mg of IL-2 at room temperature to form a uniform dispersion. Asample of 95 mg of the P(CHDM-HOP)/IL-2 paste was placed in 5 mL of 0.1M phosphate buffer (pH 7.4) at 37° C. At various time points, the samplewas centrifuged and 4 mL of the supernatant of 4 mL was withdrawn andreplaced. the withdrawn supernatant was assayed for IL-2 by use ofCTLL-2 culture, as described above. The cumulative percentage of IL-2released was calculated based on the initial amount of IL-2 blended intothe paste. At the last time point, there was IL-2 still left in thesample. FIG. 11 graphically represents the cumulative percentage ofreleased IL-2 from the P(CHDM-HOP) matrix versus time in days.

Example 15

In Vitro Release of Interleukin-2 from P(CHDM-HOP) in Tissue Culture

A paste was prepared by blending, with a spatula, lyophilized humanInterleukin-2 (“IL-2”, 18×10⁶ IU) with 240 mg of P(CHDM-HOP) at roomtemperature until homogeneous. Three 80 mg samples of theP(CHDM-HOP)/IL-2 paste were incubated with 1.5 mL of tissue culture(RPMI1640 Medium containing 10% FCS) at 37° C. with constant shaking. Atvarious time points, the samples were centrifuged, and the supernatantwas withdrawn and replaced with fresh medium. The amount of IL-2 in thewithdrawn supernatant samples was determined by an ELISA assay.

The amount of biologically active IL-2 released was assayed by thefollowing CTLL cell culture method: CTLL cells were plated in a 96-wellplate at a density of 2×10⁴ cells per well and incubated with an aliquotof the withdrawn supernatant. After two days of incubation, the rate ofcell growth was evaluated by WST-1 assay. A calibration curve wasconstructed in parallel for the assay of IL-2 release from P(CHDM-HOP)in tissue culture medium. FIG. 12 shows the calibration curvesconstructed by the sustained release of IL-2. The complete dataestablish that more than 30% of the bioactivity was retained at allpoints in time.

Example 17

In Vivo Release of Interleukin-2 from P(CHDM-HOP)

A sample of P(CHDM-HOP) was sterilized by γ-irradiation at 2.5 MRads andaseptically blended with IL-2 in the same manner as described above inExample 15. Six female Balb/c mice, 6-8 weeks of age, were injectedsubcutaneously with 50 mg of the IL-2 polymer paste sample containing3.5×10⁵ IU of IL-2. Two additional mice received the same dose of IL-2as a bolus injection, and two additional mice received blank P(CHDM-HOP)injection as a control.

At various time points, 50 μL of blood samples were collected from thetail vein. Blood samples from each group were combined and diluted withHBSS supplemented with 1% BSA. The serum was separated and assayed forIL-2 as described above. Sustained release of IL-2 was attained in vivo,with detectable levels of IL-2 present in the serum, for up to threeweeks after injection of the P(CHDM-HOP)/IL-2-loaded paste. In contrast,the IL-2 levels were undetectable after 48 hours in the mice injectedwith the IL-2 bolus. FIG. 13 graphically compares the pharmacokineticsof IL-2 administered either as a bolus or dispersed in a P(CHDM-HOP)matrix. FIG. 14 depicts the histological examination of a subcutaneousinjection site from this in vivo experiment.

Example 18

In Vivo Biocompatibility of P(trans-CHDM-HOP)

The polymer P(trans-CHDM-HOP) was synthesized as described in Example 1.To facilitate injection, ethyl alcohol was added to the polymer atlevels of 10% and 20% by volume to reduce the viscosity. Samples of 25μL of the polymer alone, 25 μL of the polymer containing 10% alcohol,and 25 μL of the polymer containing 20% alcohol, were injected into theback muscles of Sprague Dawley rats. Tissues at the injection sites wereharvested at either three or thirteen days post-injection, processed forparaffin histology, stained with heamatoxylln, eosin dye and analyzed.Medical-grade silicon oil was injected into the control group rats.

Histological examination of the back muscle sections of the ratsinjected with the polymer diluted with ethanol showed no acuteinflammatory response. The level of macrophage presence was comparableto that of the control group, which had been injected with medical-gradesilicon oil, and neutrophils were not present in any of the samplestaken on either the third or thirteenth day.

Example 18

Drug Sensitivity in an In Vitro Tumor Model

In vitro studies were done on the melanoma cell line B16/F10 using, asthe drug, doxorubicin (“DOX”), cisplatin, or 5-fluorouracil (“5-FU”).The B16/F10 cells were cultivated in the presence of differentconcentrations of DOX, cisplatin and 5-FU. According to the data, DOXshowed the strongest inhibitory effect on the cell culture, even at 0.1μg/mL.

Example 19

Controlled Delivery of Interleukin-2 and Doxorubicin from P(CHDM-HOP) inan In Vivo Tumor Model

Lyophilized interleukin-2 (“IL-2”) was purchased from Chiron, mouseInterferon-γ (“mIFN-γ”) was obtained from Boehringer Mannheim, anddoxorubicin hydrochloride (“DOX”) was obtained from Sigma. C57BL/6 mice,6-8 weeks of age, were obtained from Charles River. The aggressivemelanoma cell line B16/F10 was used to cause tumors in the mice, and thecells were maintained by weekly passages. The polymer P(CHDM-HOP) wassynthesized as described in Example 1.

Mice were randomly allocated into groups as shown below in TABLE II. Theday of tumor injection with cells of the melanoma cell line was denotedas Day 0. Each mouse received a subcutaneous injection of 50 μl (10⁵)tumor cells in phosphate buffer saline (PBS) in the left flank. On Day 3or Day 7, the tumor-bearing mice were selectively injected in the rightflank with one of the following formulations: (1) a bolus of IL-2, (2) abolus of DOX, (3) a polymer paste of IL-2, (4) a polymer paste of DOX,(5) a polymer paste containing both IL-2 and DOX, or (6) a polymer pastecontaining both IL-2 and mIFN-γ. A control group and negative controlgroup received no further injections on Day 3 or Day 7.

The bolus preparation of either IL-2 or DOX was prepared by dissolvingan appropriate amount of IL-2 or DOX in 50 μl of isotonic solution justprior to the injection. The polymer paste formulations of either IL-2,DOX, a mixture of both IL-2 and DOX, or a mixture of IL-2 and mIFN-γ,were prepared by blending 50 μl of sterilized P(CHDM-HOP) with thedrug(s) until homogeneous.

TABLE II Allocation of Groups of Mice for In Vivo Tumor Model Day ofNumber Injec- Group of Mice tion Formulation Control  5 — NothingNegative  5 — Nothing Control Bolus IL-2  8 3 0.8 × 10⁶ IU Bolus DOX  83 0.5 mg Bolus DOX  8 7 0.5 mg Paste IL-2 10 3 0.8 × 10⁶ IU Paste IL-210 7 0.8 × 10⁶ IU Paste DOX 10 3 0.5 mg Paste DOX 10 7 0.5 mg Paste(IL-2 + 10 3 0.8 × 10⁶ IU + DOX) 0.5 mg Paste (IL-2 + 10 7 0.8 × 10⁶IU + DOX) 0.5 mg Paste (IL-2 + 10 3 10⁶ IU mIFN-γ)

On Day 28 and Day 42 of tumor growth, the tumor sizes of the variousmice were measured. The results are shown below in Table III, whichshows the numerical data for the growth of tumor volumes on Day 28 andDay 42 and the number of mice who survived the experiment per druggrouping. Tumor volume was calculated as half the product of the lengthand the square of the width, in accordance with the procedure of Osiekaet al., 1981.

TABLE III CHDM-HOP Polymer as Carrier for Cytokine and Drug Delivery inMelanoma Model Tumor Volume (mm³ ± SEM*) After Initial Tumor InjectionNumber 28 days 42 days Group of Mice Number of Mice Survived Control  5No tumor No tumor Negative  5   2458 ± 1070.7 5656   Control 4 1 BolusIL-2  8  1946 ± 505.6   3282 ± 1403.3 (3d) 8 4 Bolus Dox  8 1218.9 ±304.1  3942.5 ± 1818   (3d) 8 5 Bolus Dox  8 1661.2 ± 301.8  4394.3 ±741.3  (7d) 8 3 Paste IL-2 10 934.1 ± 230     3183 ± 1223.4 (3d) 10  5Paste IL-2 10 2709.8 ± 397.3   10491 ± 2485.5 (7d) 10  3 Paste Dox 10 1410 ± 475.3 4648.9 ± 1202.2 (3d) 8 7 Paste Dox 10 1480 ± 287    3915 ±1739.7 (7d) 9 4 Paste (IL-2 + 10 657.3 ± 248.9 3362.8 ± 1120.1 DOX) (3d)8 7 Paste (IL-2 + 10 857.2 ± 243.6 3449.8 ± 1285.9 DOX) (7d) 8 5 Paste(IL-2 + 10 1217.9 ± 168.4  4469.8 ± 2018.7 mIFN-γ) (3d) 9 4 *StandardError of the Mean

Based on these measurements, the distribution of tumors sizes weregraphically represented in FIG. 15 for Day 28 (four weeks after tumorimplantation) and in FIG. 16 for Day 42 (six weeks after tumorimplantation). The graphs were subdivided into plots according to thedifferent treatments given to the tumor-bearing mice.

The results on Day 28 showed that, in comparison with the control group(tumor without treatment) and the bolus injection of IL-2, the group ofmice receiving a polymer/IL-2 paste injection successfully delayed thetumor's growth. However, for the group of mice not receiving apolymer/IL-2 paste injection until Day 7, the tumor had already becomeof substantial size by Day 7 and, accordingly, a significant reductionin tumor size was not observed.

Excellent tumor reduction was obtained with the combination of IL-2 andDOX. The average size of a tumor treated with an injection of a polymerpaste containing both IL-2 and DOX was significantly smaller than thetumor in the control group. Specifically, the average tumor size formice receiving the IL-2 and DOX/polymer paste on Day 3 was 657.3 mm³ asopposed to 2458 mm³ for the control group. Even when treatment wasdelayed until Day 7 of tumor growth, a therapeutic effect could still beseen with the polymer paste formulation containing both IL-2 and DOX.

The results on Day 42 of tumor growth also confirmed that the Day 3injection of polymer paste containing both IL-2 and DOX gave the bestresult in delaying tumor growth. The combined therapy of IL-2 and DOX ina polymer paste of the invention resulted in the occurrence of smallersized tumors in more of the test animals. According to the distributiondata shown in FIG. 15, there were four mice bearing tumors of less than1000 mm³ in the case of the combined IL-2 and DOX polymer paste therapy,as compared with only one mouse inside that range for the polymer pasteinjection of DOX alone. It was also clear that IL-2 alone did notprovide the most desirable effect, as evaluated on the 42nd day of tumorgrowth. Despite the good distribution of small tumor sizes on the 28thday, the long-time survival data appeared to be adversely affected, notonly by the progression of tumor growth at that point, but also by thelack of continued, controlled delivery of IL-2 over a longer timeperiod. With the polymer paste formulation of both IL-2 and DOX, thepolymer degraded slowly, allowing a gradual decrease in the diffusionrate of the therapeutic agent over time.

However, because of the significant difference of the distribution intumor sizes inside each group, the average tumor size as seen in TABLEIII did not provide a complete picture. A fuller appreciation of thesignificance of the treatments of the invention can be gained bycomparing data from the distribution graph of FIG. 16, which shows thedispersity in tumor sizes six weeks after tumor implantation, with thesurvival curve shown in FIG. 17, which shows the massive death of micein all groups before the Day 42 measurement, except for the groups ofanimals that had received the 3rd day injection of paste containingeither DOX alone or the combination of IL-2 and DOX. Thus, the data,taken as a whole, shows that the combined therapy of IL-2 and DOX in thepaste both significantly delayed tumor growth and extended life.

Early deaths about 3-4 days after the injections of the DOX-containingpolymer paste were thought to be due, at least in part, to the toxiceffect of DOX causing the deaths of the weaker animals. Correspondinginjections of bolus DOX did not produce early death, probably because ofthe rapid distribution and clearance from the body of the bolus-injectedDOX.

Example 20

Incorporating Paclitaxel into P(CHDM-HOP) or P(CHDM-EOP)

100 mg of each of the polymers of Example 1, p(CHDM-HOP), and Example 5,p(CHDM-EOP), was dissolved in ethanol at a concentration of about 50%.After the polymer was completely dissolved, 5 mg of paclitaxel powder (achemotherapeutic drug) was added to the solution and stirred until thepowder was completely dissolved. This solution was then poured into icewater to precipitate the polymer composition. The resulting suspensionwas centrifuged, decanted, and lyophilized overnight, to obtain aviscous gel-like product.

Example 21

In Vitro Release of Paclitaxel from P(CHDM-HOP) and P(CHDM-EOP)

In a 1.7 mL plastic micro centrifuge tube, 5 mg of both of thepaclitaxel polymer formulations of Example 20 to be tested was incubatedwith 1 mL of a buffer mixture of 80% PBS and 20% PEG 400 at 37° C. Foursamples of each formulation to be tested were prepared. At specific timepoints, approximately every day, the PBS:PEG buffer was poured off forpaclitaxel analysis by HPLC, and fresh buffer was added to themicrocentrifuge tube. The release study was terminated at day 26, atwhich point the remaining paclitaxel in the polymer was extracted with asolvent to do a mass balance on paclitaxel.

The resulting release curves for the release of paclitaxel from bothpolymers are shown in FIG. 18. The total paclitaxel recovery was 65% forthe P(CHDM-HOP) formulation and 75% for the P(CHDM-EOP) formulation.

Example 22

Preparation of P(CHDM-HOP)/Lidocaine Paste

A paste of P(CHDM-HOP) and lidocaine (base; Sigma, Cat. # L-7757) wasprepared by mechanically mixing as follows: 60 mg of P(CHDM-HOP) and 16mg of lidocaine were weighed onto a glass microscope slide. The polymerand the lidocaine drug were thoroughly mixed with a spatula until auniform mixture was obtained. The resulting lidocaine/polymer mixtureformed a 24% w/w lidocaine paste with the lidocaine remaining as asolid.

Example 23

In Vitro Release of Lidocaine from P(CHDM-HOP)

Approximately 10 mg of the lidocaine/polymer mixture prepared above inExample 22 was placed in 2.0 mL of phosphate buffered solution (PBS)(0.1 M, pH 7.4) at 37° C. on a shaker. The buffer was replaced atspecific time points, and samples were withdrawn. The lidocaine releasedfrom the polymer into the samples was assayed by HLPC.

The results of three different samples of the lidocaine/polymer mixtureare graphically represented in FIG. 19. FIG. 20A displays the cumulativeamount of lidocaine released as a function of incubation time and FIG.20B shows the cumulative amount of lidocaine released over the squareroot of time, demonstrating that approximately 90% of the drug wasreleased within one week. The linear relationship between the amount oflidocaine released and the square root of time indicated that themechanism of drug release was mainly through diffusion during the testperiod.

Example 24

Release of Lidocaine from P(CHDM-HOP)in a Rat Sciatic Nerve Model InVivo

Single jugular catheters were inserted into Male Sprague-Dawley rats,approximately 150-200 g in weight. The rats were anesthetized by i.p.injection with about 0.3-0.4 mL of an anesthetic cocktail (25 mg/mLketamine, 2.5 mg/mL xylazine and 14.5% 200 proof ethanol). The sciaticnerve of the animal was identified. Each animal received a singleinjection of either 25 mg or 50 mg of lidocaine in either P(CHDM-HOP) oras a saline solution into its sciatic nerve to block the nerve. Controlgroup rats received an equivalent amount of blank polymer injected intotheir sciatic nerves.

The rats were observed over time, and scores were assigned to both motorand nociceptive responses as follows:

Motor response and function

normal motor function=0,

slight foot drag=1,

moderate foot drag=2, and

no motor function=3;

Nociceltive response and function

normal nociceptive response=0,

slightly delayed nociceptive response=1,

delayed nociceptive response =2, and

no nociceptive response =3.

Blood samples were also collected at specific time points, and theplasma concentration of lidocaine was assayed by HLPC.

FIG. 22 shows the plot of percent of maximum motor function effectversus time after injection with 25 mg of lidocaine in P(CHDM-HOP) or insaline solution. A maximum percentage effect of 100% on this graphrepresents a score of “3” for “no motor response.” All of the ratsinjected with lidocaine-containing preparations exhibited complete motorblock during the first hour following injection. Table IV belowsummarizes the duration of the lidocaine blocking effects followinginjection of lidocaine in saline solution or in P(CHDM-HOP).

TABLE IV Duration of Lidocaine Reaction Following Injection of Lidocainein Saline Solution or P(CHDM-HOP) Sensory Function Motor FunctionLidocaine Complete Partial Complete Partial Formulation Block BlockBlock Block Blank P(CHDM-HOP) 0 0 0 0 25 mg Saline  2 hrs  48 hrs 1 hr 27 hrs solution 25 mg in  54 hrs 198 hrs 1 hr 198 hrs P(CHDM-HOP) 50 mgin 119 hrs 265 hrs  2 hrs 240 hrs P(CHDM-HOP)

The duration of motor function blockage from the lidocaine inP(CHDM-HOP) was clearly longer than that achieved by the lidocainesaline solution. However, the extent of motor function blockage was onlypartial, in that a rat could still move its leg with a slight drag. Itwas also noted that the increase in complete motor blockage was minimaleven at the higher lidocaine concentration of 50 mg of lidocaine.

Table V below shows the percentage of rats exhibiting complete blockageof the nociceptive response following the administration of 25 mg oflidocaine either as a saline solution or in P(CHDM-HOP).

TABLE V Percentage of Rats with Complete Nociceptive Response Percentageof Rats with Complete Block of Nociceptive Response 25 mg Lidocaine 25mg Lidocaine Time in P(CHDM-HOP) in Saline Solution 0.5 hrs  100 100   3hrs 100 78   6 hrs 100 50  24 hrs 100 0 30 hrs  78 0 48 hrs 100 0 51 hrs100 0 54 hrs 100 0 72 hrs  78 0 99 hrs  78 0 119 hrs   50 0 125 hrs   780 143 hrs   50 0 149 hrs   50 0

Compared with the lidocaine/saline solution, the lidocaine/P(CHDM-HOP)formulation prolonged the sensory blocking effect of lidocainesignificantly.

FIG. 21 plots the percentage of maximum nociceptive effect versus timeafter injection with 25 mg of lidocaine in either P(CHDM-HOP) or salinesolution. The maximum percentage effect of 100% on this graphrepresented a score of “3”, i.e., “no nociceptive response.” Again,compared with the data from the lidocaine in saline solution, asignificantly prolonged local anesthetic effect was observed in thelidocaine/P(CHDM-HOP) group.

It was noted that recovery from the motor block occurred well beforecomplete recovery from the sensory block in both the lidocaine/salinesolution and the lidocaine/P(CHDM-HOP) formulations. The rats couldoften move around with their hind limb and still exhibit no apparentresponse to pain stimuli. Because complete responsiveness to nociceptionwas recovered well after the recovery of motor function, pharmaceuticalcompositions of the invention are believed to be well-suited for theclinical administration of local anesthetics and the management ofchronic pain.

FIG. 23 shows the lidocaine concentration in plasma following injectionof 25 mg of lidocaine in saline solution, 25 mg of lidocaine inP(CHDM-HOP), and 50 mg of lidocaine in P(CHDM-HOP). By increasing theconcentration of lidocaine in the polymer formulation, the duration ofthe anesthetic function was extended with a minimal increase in thelidocaine concentration in systemic circulation, indicating thatdiffusion of the majority of the drug was restricted to the local area.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of at the invention, and all suchmodifications are intended to be a included within the scope of thefollowing claims.

We claim:
 1. A biodegradable, flowable or flexible polymer compositioncomprising (a) a polymer having the recurring monomeric units shown informula I:

wherein: each of R and R′ is independently straight or branchedaliphatic, either unsubstituted or substituted with one or morenon-interfering substituents; L is a divalent cycloaliphatic group,wherein the cyclic portion of said cycloaliphatic group is not aromaticor heterocyclic in nature; R″ is selected from the group consisting ofH, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and n is5 to 1,000; and (b) at least one biologically active substance, whereinsaid biodegradable polymer composition is biocompatible both before andupon biodegradation.
 2. The polymer composition of claim 1 wherein eachof R and R′ is a branched or straight chain alkylene group having fromone to seven carbon atoms.
 3. The polymer composition of claim 1 whereineach of R and R′ is a methylene group or an ethylene group.
 4. Thepolymer composition of claim 1 wherein R″ is an alkyl group, an alkoxygroup, a phenyl group, a phenoxy group, or a heterocycloxy group.
 5. Thepolymer composition of claim 1 wherein R″ is an alkoxy group.
 6. Thepolymer composition of claim 1 wherein n is 5 to
 500. 7. The polymercomposition of claim 1 wherein L is cyclohexylene.
 8. The polymercomposition of claim 1 wherein said polymer comprises additionalbiocompatible monomeric units or is blended with other biocompatiblepolymers.
 9. The polymer composition of claim 1 wherein said compositionalso comprises at least one biologically active substance.
 10. Thepolymer composition of claim 1 wherein said biologically activesubstance is selected from the group consisting of peptides,polypeptides, proteins, amino acids, polysaccharides, growth factors,hormones, anti-angiogenesis factors, interferons or cytokines, antigenicmaterials, and pro-drugs of these substances.
 11. The polymercomposition of claim 1 wherein said biologically active substance is atherapeutic drug or pro-drug.
 12. The polymer composition of claim 11wherein said drug is selected from the group consisting ofanti-neoplastic agents, local anesthetics, antibiotics, anti-virals,anti-fungals, anti-inflammatories, anticoagulants, antigenic materialssuitable for vaccine applications, and pro-drugs of these substances.13. The polymer composition of claim 1 wherein said polymer compositionis non-toxic and results in minimal tissue irritation when injected oris otherwise placed into intimate contact with vasculated tissues.
 14. Abiodegradable, flowable or flexible polymer composition comprising apolymer having the recurring monomeric units shown in formula I:

wherein: each of R and R′ is independently straight or branchedaliphatic, either unsubstituted or substituted with one or morenon-interfering substituents; L is a divalent cycloaliphatic group,wherein the cyclic portion of said cycloaliphatic group is not aromaticor heterocyclic in nature; R″ is selected from the group consisting ofH, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and n is5 to 1,000, or alternatively one or more of R, R′ and R″ is abiologically active substance in a form capable of being released in aphysiological environment; wherein said biodegradable polymercomposition is biocompatible both before and upon biodegradation. 15.The polymer composition of claim 14 wherein each of R and R′ is abranched or straight chain alkylene group having from one to sevencarbon atoms.
 16. The polymer composition of claim 14 wherein each of Rand R′ is a methylene group or an ethylene group.
 17. The polymercomposition of claim 14 wherein R″ is an alkyl group, an alkoxy group, aphenyl group, a phenoxy group, or a heterocycloxy group.
 18. The polymercomposition of claim 14 wherein R″ is an alkoxy group.
 19. The polymercomposition of claim 14 wherein n is 5 to
 500. 20. The polymercomposition of claim 14 wherein L is cyclohexylene.
 21. The polymercomposition of claim 14 wherein said polymer comprises additionalbiocompatible monomeric units or is blended with other biocompatiblepolymers.
 22. The polymer composition of claim 14 wherein R″ is abiologically active substance.
 23. The polymer composition of claim 14wherein either R or R′ is a biologically active substance.
 24. Thepolymer composition of claim 14 wherein said biologically activesubstance is selected from the group consisting of peptides,polypeptides, proteins, amino acids, polysaccharides, growth factors,hormones, anti-angiogenesis factors, interferons or cytokines, antigenicmaterials, and pro-drugs of these substances.
 25. The polymercomposition of claim 14 wherein said biologically active substance is atherapeutic drug or pro-drug.
 26. The polymer composition of claim 25wherein said drug is selected from the group consisting ofanti-neoplastic agents, local anesthetics, antibiotics, anti-virals,anti-fungals, anti-inflammatories, anticoagulants, antigenic materialssuitable for vaccine applications, and pro-drugs of these substances.27. The polymer composition of claim 14 wherein said polymer compositionis non-toxic and results in minimal tissue irritation when injected oris otherwise placed into intimate contact with vasculated tissues. 28.The polymer composition of claim 11 wherein said drug is selected fromthe group consisting of β-adrenergic blocking agents, anabolic agents,androgenic steroids, antacids, anti-asthmatic agents, anti-allergenicmaterials, anti-arrhythmics, anti-cholesterolemic and anti-lipid agents,anti-cholinergics and sympathomimetics, anti-convulsants,anti-diarrheals, anti-emetics, anti-hypertensive agents, anti-infectiveagents, anti-malarials, anti-manic agents, anti-nauseants, anti-obesityagents, anti-parkinsonian agents, anti-pyretic and analgesic agents,anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents,anti-anginal agents, antihistamines, anti-tussives, appetitesuppressants, benzophenanthridine alkaloids, biologicals, cardioactiveagents, cerebral dilators, coronary dilators, decongestants, diuretics,diagnostic agents, erythropoietic agents, estrogens, expectorants,gastrointestinal sedatives, humoral agents, hyperglycemic agents,hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineralsupplements, miotics, mucolytic agents, neuromuscular drugs, nutritionalsubstances, peripheral vasodilators, progestational agents,prostaglandins, psychic energizers, psychotropics, sedatives,stimulants, thyroid and anti-thyroid agents, tranquilizers, uterinerelaxants, vitamins, and pro-drugs of these substances.
 29. The polymercomposition of claim 25 wherein said drug is selected from the groupconsisting of β-adrenergic blocking agents, anabolic agents, androgenicsteroids, antacids, anti-asthmatic agents, anti-allergenic materials,anti-arrhythmics, anti-cholesterolemic and anti-lipid agents,anti-cholinergics and sympathomimetics, anti-convulsants,anti-diarrheals, anti-emetics, anti-hypertensive agents, anti-infectiveagents, anti-malarials, anti-manic agents, anti-nauseants, anti-obesityagents, anti-parkinsonian agents, anti-pyretic and analgesic agents,anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents,anti-anginal agents, antihistamines, anti-tussives, appetitesuppressants, benzophenanthridine alkaloids, biologicals, cardioactiveagents, cerebral dilators, coronary dilators, decongestants, diuretics,diagnostic agents, erythropoietic agents, estrogens, expectorants,gastrointestinal sedatives, humoral agents, hyperglycemic agents,hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineralsupplements, miotics, mucolytic agents, neuromuscular drugs, nutritionalsubstances, peripheral vasodilators, progestational agents,prostaglandins, psychic energizers, psychotropics, sedatives,stimulants, thyroid and anti-thyroid agents, tranquilizers, uterinerelaxants, vitamins, and pro-drugs of these substances.
 30. The polymercomposition of claim 1, wherein said biologically active substance islidocaine.
 31. The polymer composition of claim 1, wherein saidbiologically active substance is paclitaxel.
 32. The polymer compositionof claim 14, wherein said biologically active substance is lidocaine.33. The polymer composition of claim 14, wherein said biologicallyactive substance is paclitaxel.